Methods for manufacturing dosage forms

ABSTRACT

Systems, methods and apparatuses for manufacturing dosage forms, and to dosage forms made using such systems, methods and apparatuses are provided. Novel compression, thermal cycle molding, and thermal setting molding modules are disclosed. One or more of such modules may be linked, preferably via novel transfer device, into an overall system for making dosage forms.

FIELD OF THE INVENTION

This invention relates generally to systems, methods and apparatuses formanufacturing dosage forms, and to dosage forms made using such systems,methods and apparatuses.

BACKGROUND OF THE INVENTION

A variety of dosage forms, such as tablets, capsules and gelcaps areknown in the pharmaceutical arts. Tablets generally refer to relativelycompressed powders in various shapes. One type of elongated,capsule-shaped tablet is commonly referred to as a “caplet.” Capsulesare typically manufactured using a two piece gelatin shell formed bydipping a steel rod into gelatin so that the gelatin coats the end ofthe rod. The gelatin is hardened into two half-shells and the rodextracted. The hardened half-shells are then filled with a powder andthe two halves joined together to form the capsule. (See generally,HOWARD C. ANSEL ET AL ., Pharmaceutical Dosage Forms and Drug DeliverySystems (7th Ed. 1999).)

Gelatin-coated tablets, commonly known as geltabs and gelcaps, are animprovement on gelatin capsules and typically comprise a tablet coatedwith a gelatin shell. Several well known examples of gelcaps are McNeilConsumer Healthcare's acetaminophen based products sold under the tradename Tylenol®. U.S. Pat. Nos. 4,820,524; 5,538,125; 5,228,916;5,436,026; 5,679,406; 5,415,868; 5,824,338; 5,089,270; 5,213,738;5,464,631; 5,795,588; 5,511,361; 5,609,010; 5,200,191; 5,459,983;5,146,730; 5,942,034 describe geltabs and gelcaps and methods andapparatuses for making them. Conventional methods for forming gelcapsare generally performed in a batchwise manner using a number of standalone machines operating independently. Such batch processes typicallyinclude the unit operations of granulating, drying, blending, compacting(e.g., in a tablet press), gelatin dipping or enrobing, drying, andprinting.

Unfortunately, these processes have certain drawbacks. For example,because these systems are batch processes, each of the variousapparatuses employed is housed in a separate clean room that must meetFDA standards. This requires a relatively large amount of capital interms of both space and machinery. A process that would increase andstreamline production rates would therefore provide many economicbenefits including a reduction in the size of facilities needed to massproduce pharmaceutical products. Generally, it would be desirable tocreate a continuous operation process, as opposed to a batch process,for formation of gelcaps and other dosage forms.

Furthermore, gel dipping and drying operations are in general relativelytime consuming. Thus, a process that simplifies the gelatin coatingoperation in particular and reduces drying time would also beadvantageous.

Current equipment for making gelcaps and geltabs is designed to producethese forms only according to precise specifications of size and shape.A more versatile method and apparatus, which could be used to produce avariety of dosage forms to deliver pharmaceuticals, nutritionals, and/orconfections, would therefore also be advantageous.

Accordingly, applicants have now discovered that a wide variety ofdosage forms, including compressed tablets, gelcaps, chewable tablets,liquid fill tablets, high potency dosage forms, and the like, some ofwhich in and of themselves are novel, can be made using unique operatingmodules. Each operating module performs distinct functions, andtherefore may be used as a stand alone unit to make certain dosageforms. Alternatively, two or more of the same or different operatingmodules may be linked together to form a continuous process forproducing other dosage forms. In essence, a “mix and match” system forthe production of dosage forms is provided by the present invention.Preferably, the operating modules may be linked together as desired tooperate as a single continuous process.

SUMMARY OF THE INVENTION

In a first embodiment, the invention provides a method of making dosageforms, comprising the steps of: a) compressing a powder into acompressed dosage form in a compression module; b) transferring saidcompressed dosage form to a thermal cycle molding module; c) molding aflowable material around said compressed dosage form in said thermalcycle molding module; and d) hardening said flowable material so as toform a coating over said compressed dosage form; wherein steps (a)through (d) are linked together such that essentially no interruptionoccurs between said steps.

The invention also provides a method of making dosage forms, comprisingthe steps of: a) compressing a first powder into a compressed dosageform in a first compression module; b) transferring said compresseddosage form to a thermal cycle molding module; c) molding a flowablematerial around said compressed dosage form in said thermal cyclemolding module; d) hardening said flowable material so as to form acoating over said compressed dosage form; e) transferring said coatedcompressed dosage form to a second compression module; and f)compressing a second powder around said coated compressed dosage form insaid second compression module to form a compressed, coated, compresseddosage form; wherein steps (a) through (f) are linked together such thatessentially no interruption occurs between said steps.

The invention further provides a method of making a dosage form,comprising the steps of: a) forming an insert; b) transferring saidinsert to a thermal cycle molding module; c) molding a flowable materialaround said insert in said thermal cycle molding module; and d)hardening said flowable material so as to form a coating over saidinsert; wherein steps (a) through (d) are linked together such thatessentially no interruption occurs between said steps.

The invention further provides a method of making a dosage form,comprising the steps of: a) forming at least two inserts; b)transferring said inserts to a thermal cycle molding module; c) moldinga flowable material around said inserts in said thermal cycle moldingmodule; and d) hardening said flowable material so as to form a coatingover said inserts to form a dosage form comprising at least two insertssurrounded by a coating; wherein steps (a) through (d) are linkedtogether such that essentially no interruption occurs between saidsteps.

The invention also provides a method of making dosage forms, comprisingthe steps of: a) forming an insert; b) transferring said insert to acompression module; c) compressing a powder around said insert into acompressed dosage form in a compression module; wherein steps (a)through (c) are linked together such that essentially no interruptionoccurs between said steps.

The invention also provides a linked apparatus for making dosage formscontaining a medicant, comprising: a) a compression module having meansfor forming compressed dosage forms by compressing a powder containingsaid medicant; b) a transfer device having means for continuouslytransferring said compressed dosage forms from said compression moduleto a thermal cycle molding module; and c) a thermal cycle molding modulehaving means for continuously molding a coating of flowable materialover said compressed dosage forms.

The invention further provides an apparatus for making dosage formscontaining a medicant, comprising: a) a first rotor comprising aplurality of die cavities disposed around the circumference thereof soas to be carried around a first circular path by said rotor, each ofsaid die cavities having an opening for receiving powder and at leastone punch mounted for displacement into said die cavity, wherebydisplacement of said punch into said die cavity compresses powdercontained in said die cavity into a compressed dosage form; b) a secondrotor comprising a plurality of mold cavities disposed around thecircumference thereof so as to be carried around a second circular pathby said second rotor, each of said mold cavities capable of enclosing atleast a portion of a compressed dosage form and capable of receivingflowable material so as to coat said portion of said compressed dosageform enclosed by said mold cavity; and c) a transfer device fortransferring compressed dosage forms from said first rotor to saidsecond rotor, said transfer device comprising a plurality of transferunits guided around a third path, a first portion of said third pathbeing coincident with said first circular path and a second portion ofsaid third path being coincident with said second circular path.

The invention also provides a method of forming compressed dosage forms,comprising: a) placing a supply of powder in flow communication with adie, said die comprising a die cavity therein in flow communication witha filter; b) applying suction to said die cavity so as to cause powderto flow into said die cavity, said suction being applied to said diecavity through said filter; c) isolating said filter from said powder insaid die cavity; and d) compressing said powder in said die cavity so asto form a compressed dosage form while said filter is isolatedtherefrom.

The invention also provides an apparatus for forming compressed dosageforms, comprising: a) a suction source; b) a die cavity having (i) afirst port for placing said die cavity in flow communication with saidsuction source, whereby said suction source applies suction to said diecavity, and (ii) a second port for placing said die cavity in flowcommunication with a supply of powder, whereby said suction sourceassists said powder in flowing into said die cavity; (c) a filterdisposed between said suction source and said second port, wherebysuction is applied to said die cavity through said filter; and (d) apunch for compressing said powder in said die cavity so as to form saidcompressed dosage forms.

The invention also provides an apparatus for forming compressed dosageforms from a powder, comprising a) a die table having a plurality of diecavities therein, said die cavities being arranged in multiple,concentric rows around the perimeter of said die table; b) punchesaligned with and insertable into said die cavities for compressing saidpowder into compressed dosage forms in each of said die cavities; and c)rollers aligned with each of said concentric rows of die cavities forpressing said punches into said die cavities, each roller being sizedsuch that the dwell time under compression of all of said punches isequal.

The invention also provides a rotary compression module for formingcompressed dosage forms from a powder, comprising a) a single fill zone;b) a single compression zone; c) a single ejection zone; d) a circulardie table having a plurality of die cavities therein; and e) punchesaligned with and insertable into said die cavities for compressing saidpowder into compressed dosage forms in each of said die cavities;wherein the number of die cavities in said module is greater than themaximum number of die cavities that can be arranged in a single circlearound the circumference of a similar die table having the same diameteras the circular die table, and wherein the dwell time under compressionof all of said punches is equal.

The invention further provides compressed dosage forms made from apowder having a minimum orifice diameter of flowablility greater thanabout 10 mm as measured by the Flowdex test, the relative standarddeviation in weight of said compressed dosage forms being less thanabout 2%, and made using a linear velocity at the die of at least about230 cm/sec.

The invention also provides compressed dosage forms made from a powderhaving a minimum orifice diameter of flowablility greater than about 15mm as measured by the Flowdex test, the relative standard deviation inweight of said compressed dosage forms being less than about 2%, andmade using a linear velocity at the die of at least about 230 cm/sec.

The invention also provides compressed dosage forms made from a powderhaving a minimum orifice diameter of flowablility greater than about 25mm as measured by the Flowdex test, the relative standard deviation inweight of said compressed dosage forms being less than about 2%, andmade using a linear at the die velocity of at least about 230 cm/sec.

The invention also provides compressed dosage forms made from a powderhaving a minimum orifice diameter of flowablility greater than about 10mm as measured by the Flowdex test, the relative standard deviation inweight of said compressed dosage forms being less than about 1%, andmade using a linear velocity at the die of at least about 230 cm/sec.

The invention also priovides compressed dosage forms made from a powderhaving a minimum orifice diameter of flowablility greater than about 10mm as measured by the Flowdex test, the relative standard deviation inweight of said compressed dosage forms being less than about 2%, andmade using a linear velocity at the die of at least about 115 cm/sec.

The invention also provides compressed dosage forms made from a powderhaving an average particle size of about 50 to about 150 microns andcontaining at least about 85 percent by weight of a medicant, therelative standard deviation in weight of said compressed dosage formsbeing less than about 1%.

The invention also provides compressed dosage forms containing at leastabout 85 percent by weight of a medicant and being substantially free ofwater soluble polymeric binders, the relative standard deviation inweight of said compressed dosage forms being less than about 2%.

The invention also provides compressed dosage forms containing at leastabout 85 percent by weight of a medicant and being substantially free ofwater soluble polymeric binders, the relative standard deviation inweight of said compressed dosage forms being less than about 1%.

The invention also provides compressed dosage forms containing at leastabout 85 percent by weight of a medicant selected from the groupconsisting of acetaminophen, ibuprofen, flurbiprofen, ketoprofen,naproxen, diclofenac, aspirin, pseudoephedrine, phenylpropanolamine,chlorpheniramine maleate, dextromethorphan, diphenhydramine, famotidine,loperamide, ranitidine, cimetidine, astemizole, terfenadine,fexofenadine, loratadine, cetirizine, antacids, mixtures thereof andpharmaceutically acceptable salts thereof, and being substantially freeof water soluble polymeric binders, the relative standard deviation inweight of said compressed dosage forms being less than about 2%.

The invention also provides compressed dosage forms containing at leastabout 85 percent by weight of a medicant and being substantially free ofhydrated polymers, the relative standard deviation in weight of saidcompressed dosage forms being less than about 2%.

The invention also provides compressed dosage forms containing at leastabout 85 percent by weight of a medicant and being substantially free ofhydrated polymers, the relative standard deviation in weight of saidcompressed dosage forms being less than about 1%.

The invention also provides compressed dosage forms containing at leastabout 85 percent by weight of a medicant selected from the groupconsisting of acetaminophen, ibuprofen, flurbiprofen, ketoprofen,naproxen, diclofenac, aspirin, pseudoephedrine, phenylpropanolamine,chlorpheniramine maleate, dextromethorphan, diphenhydramine, famotidine,loperamide, ranitidine, cimetidine, astemizole, terfenadine,fexofenadine, loratadine, cetirizine, antacids, mixtures thereof andpharmaceutically acceptable salts thereof,and being substantially freeof hydrated polymers, the relative standard deviation in weight of saidcompressed dosage forms being less than about 2%.

The invention also provides a method of making a dosage form containinga first medicant, which comprises a) injecting through a nozzle aflowable material containing said first medicant into a mold cavity; andb) hardening said flowable material into a molded dosage form having ashape substantially the same as the mold cavity.

The invention provides a method of making a molded dosage form whichcomprises a) heating a flowable material; b) injecting said flowablematerial through an orifice into a mold cavity; and c) hardening saidflowable material into a molded dosage form having a shape substantiallythe same as the mold cavity; wherein said hardening step (c) comprisescooling said flowable material and wherein said mold cavity is heatedprior to said injecting step (b) and cooled during said hardening step(c).

The invention also provides a method of coating a substrate, comprisingthe steps of: a) enclosing at least a portion of said substrate in amold cavity; b) injecting a flowable material into said mold cavity soas to coat at least a portion of said substrate with said flowablematerial; and c) hardening said flowable material to form a coating overat least a portion of said substrate.

The invention also provides a method of applying at least one flowablematerial to a substrate having first and second portions comprising:masking said first portion of said substrate; exposing said secondportion to a mold cavity; injecting said flowable material onto saidsecond portion; and hardening said flowable material on said secondportion of said substrate.

The invention also provides a method of applying at least one flowablematerial to a substrate having first and second portions comprising:exposing said first portion to a first mold cavity; injecting saidflowable material onto said first portion; hardening said flowablematerial on said first portion of said substrate; retaining said firstportion in said first mold cavity.

The invention provides a method of coating a substrate with first andsecond flowable materials, comprising the steps of: a) enclosing a firstportion of said substrate in a first mold cavity; b) injecting a firstflowable material into said first mold cavity so as to coat said firstportion with said first flowable material; c) hardening said firstflowable material to form a coating over said first portion; d)enclosing a second portion of said substrate in a second mold cavity; e)injecting a second flowable material into said second mold cavity so asto coat said second portion with said second flowable material; and f)hardening said second flowable material to form a coating over saidsecond portion.

The invention provides an apparatus for molding substrates comprising aplurality of mold cavities, each mold cavity having an internal surfaceand comprising an orifice for delivering flowable material to said moldcavity, said orifice being matable with a valve tip that in its closedposition forms part of said internal surface.

The invention also provides an apparatus for molding substratescomprising a plurality of mold cavities, a heat source, a heat sink, anda temperature control system, said temperature control system comprisinga tubing system disposed proximal to said mold cavities and connected tosaid heat source and said heat sink for circulating heat transfer fluidthrough said heat source, through said heat sink, and proximal to saidmold cavities, such that said mold cavities may be heated and cooled bysaid heat transfer fluid.

The invention also provides a nozzle system for a molding apparatus,comprising a nozzle and an ejector means, said nozzle surrounding andbeing concentric with said ejector means.

The invention provides an apparatus for coating compressed dosage forms,comprising: a) a mold cavity for enclosing at least a first portion ofsaid compressed dosage form; b) means for injecting a flowable materialinto said mold cavity to coat at least said first portion of saidcompressed dosage form with said flowable material; and c) means forhardening said flowable material so as to form a coating over at leastsaid first portion said compressed dosage form.

The invention also provides an apparatus for coating a compressed dosageform having a first portion and a second portion, comprising: a) a moldcavity for enclosing said first portion of said compressed dosage form;b) a nozzle for injecting a flowable material into said mold cavity tocoat said first portion of said compressed dosage form with saidflowable material; c) a temperature control system capable of heatingand cooling said mold cavity; and d) an elastomeric collet for sealingsaid second portion of said compressed dosage form while said firstportion of said compressed dosage form is being coated.

The invention also provides a molding module for molding coatings ontocompressed dosage forms, comprising a rotor capable of rotating about acentral axis and a plurality of mold units mounted thereon, each moldunit comprising: a) a mold cavity for enclosing at least a first portionof said compressed dosage form; b) means for injecting a flowablematerial into said mold cavity to coat at least said first portion ofsaid compressed dosage form with said flowable material; and c) meansfor hardening said flowable material so as to form a coating over atleast said first portion said compressed dosage form.

The invention also provides a molding module for coating a compresseddosage form having a first portion and a second portion, comprising arotor capable of rotating about a central axis and a plurality of moldunits mounted thereon, each mold unit comprising: a) a mold cavity forenclosing said first portion of said compressed dosage form; b) a nozzlefor injecting a flowable material into said mold cavity to coat saidfirst portion of said compressed dosage form with said flowablematerial; c) a temperature control system capable of heating and coolingsaid mold cavity; and d) an elastomeric collet for sealing said secondportion of said compressed dosage form while said first portion of saidcompressed dosage form is being coated.

The invention also provides an apparatus for coating compressed dosageforms, comprising: a) a lower retainer comprising a plurality of colletsmounted therein; b) a center mold assembly comprising first and secondgroups of insert assemblies mounted on opposing sides thereof, each ofsaid insert assemblies of said first group aligned with and facing oneof said collets, said lower retainer and said center mold assemblymounted for relative movement so as to bring said first group of insertassemblies into engagement with said collets; c) an upper mold assemblycomprising upper insert assemblies mounted therein, each of said upperinsert assemblies aligned with and facing one of said insert assembliesof said second group, said upper mold assembly and said center moldassembly mounted for relative movement so as to bring said upper insertassemblies into engagement with said second group of insert assemblies;d) a supply of flowable material; and e) a first passage placing saidsupply of flowable material in flow communication with said first andsecond group of insert assemblies, and a valve actuator assembly forcontrolling the flow of said flowable material to said first and secondgroups of insert assemblies.

The invention also provides a dosage form comprising a substrate havingan injection molded coating surrounding at least a portion of thesubstrate.

The invention also provides a dosage form comprising a substrate havinga thermal cycle molded material disposed on at least a portion of thesubstrate.

The invention also provides a dosage form comprising a substrate havinga coating thereon, said coating having a thickness of about 100 to about400 microns; the relative standard deviation in thickness of saidcoating being less than 30%; wherein said coating is substantially freeof humectants.

The invention also provides a dosage form comprising a tablet having acoating thereon, said coating having a thickness of about 100 to about400 microns, wherein the relative standard deviation in thickness ofsaid dosage form is not more than about 0.35%; and wherein said coatingis substantially free of humectants.

The invention also provides an apparatus for transferring substratesfrom a first location to a second location, comprising: a) a flexibleconveying means; b) a plurality of transfer units mounted to saidconveying means, said transfer units being capable of holding saidsubstrates; c) a cam track defining a path between said first and secondlocations; and d) means for driving said conveying means along said camtrack.

The invention also provides an apparatus for transferring substratesfrom a first operating module comprising a first rotor adapted to carrysaid substrates around a first circular path to a second operatingmodule comprising a second rotor adapted to carry said substrates arounda second circular path, said apparatus comprising a flexible conveyingmeans traversing a third path, a first portion of said third path beingcoincident with a portion of said first circular path and a secondportion of said third path being coincident with a portion of saidsecond circular path.

The invention also provides a method for making an insert, comprisingthe steps of: a) injecting a starting material in flowable formcomprising a medicant and a thermal setting material into a moldingchamber having a shape; b) solidifying said starting material so as toform a solid insert having the shape of said molding chamber; and c)ejecting said solid insert from said molding chamber, wherein said stepsoccur during rotation of said molding chambers about a central axis.

The invention provides an apparatus for molding substrates from astarting material in flowable form, comprising a plurality of moldingchambers and a plurality of nozzles aligned with said molding chambers,said molding chambers and said nozzles mounted on a rotor capable ofrotation about a central axis, said nozzles being displaceable in adirection parallel to said central axis, such that as said rotorrotates, said nozzles engage and disengage said molding chambers.

The invention also provides a dosage form comprising a medicant, saiddosage form prepared by molding a flowable material, said dosage formhaving no more than one axis symmetry and being substantially freevisible defects.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B are examples of dosage forms made according to theinvention.

FIG. 2 is a flow chart of an embodiment of the method of the invention.

FIG. 3 is a plan view, partially schematic, of a system formanufacturing dosage forms according to the invention.

FIG. 4 is an elevational view of the system shown in FIG. 3.

FIG. 5 is a three dimensional view of a compression module and transferdevice according to the invention.

FIG. 6 is top view of a portion of the compression module shown in FIG.5.

FIG. 7 depicts the path of one row of punches of a compression moduleduring a revolution of the compression module.

FIG. 8 depicts the path of another row of punches of the compressionmodule during a revolution of the compression module.

FIG. 9 is a partial cross-section of a compression module duringcompression.

FIG. 10 is a cross-section taken through line 10—10 of FIG. 9.

FIG. 11 is a cross-section taken through line 11—11 of FIG. 10.

FIG. 12 is an enlarged view of the die cavity area circled in FIG. 11.

FIG. 12A shows another embodiment of a die cavity of the compressionmodule.

FIG. 13 is a top view of the fill zone of the compression module.

FIG. 14 is a cross-sectional view of a portion of the fill zone of thecompression module.

FIG. 15 is a cross section taken through line 15—15 of FIG. 6.

FIG. 16 is a view taken along an arc of the compression module duringcompression.

FIGS. 17A–C illustrate one embodiment of a “C” frame for the compressionrollers.

FIGS. 18A–C illustrate another embodiment of a “C” frame for thecompression rollers.

FIGS. 19A–C illustrate a preferred embodiment of a “C” frame for thecompression rollers.

FIG. 20 is a top view of the purge zone and the fill zone of thecompression module.

FIG. 21 is a cross-section taken through line 21—21 of FIG. 20.

FIG. 22 is a cross-section taken through line 22—22 of FIG. 20.

FIG. 23 illustrates an embodiment of a powder recovery system for thecompression module.

FIG. 24 is a cross-section taken along line 24—24 of FIG. 23.

FIG. 25 shows an alternative embodiment of a powder recovery system forthe compression module.

FIGS. 26A–C illustrate one embodiment of a thermal cycle molding moduleaccording to the invention in which dosage forms per se are made.

FIGS. 27A–C illustrate another embodiment of a thermal cycle moldingmodule in which a coating is applied to a substrate.

FIGS. 28A–C illustrate a preferred embodiment of a thermal cycle moldingmodule in which a coating is applied to a substrate.

FIG. 29 is a three dimensional view of a thermal cycle molding moduleaccording to the invention.

FIG. 30 depicts a series of center mold assemblies in a thermal cyclemolding module.

FIG. 31 is a cross-section taken along line 31—31 of FIG. 30.

FIGS. 32–35 depict the opening, rotation and closing of the center moldassembly with the lower retainer and upper mold assembly.

FIGS. 36 and 37 are cross-sectional views of a lower retainer of athermal cycle molding module.

FIGS. 38 and 39 are top views of an elastomeric collet of a lowerretainer.

FIG. 39A is an enlarged view of a portion of the elastomeric colletshown in FIG. 39.

FIG. 40 shows a preferred cam system for the center mold assembly of thethermal molding module.

FIG. 41 is a cross-section of the center mold assembly showing oneembodiment of a valve actuator assembly therefor.

FIG. 42 is a cross-section of the center mold assembly showing oneembodiment of an air actuator assembly therefor.

FIGS. 43 and 46 are cross-sectional views of a portion of the centermold assembly showing first and second manifold plates.

FIG. 44 is a cross-section taken along line 44—44 of FIG. 43.

FIG. 45 is a cross-section taken along line 45—45 of FIG. 43.

FIG. 47 is a cross-section taken along line 47—47 of FIG. 46.

FIGS. 48–50 are cross-sectional views of a preferred nozzle system of acenter mold assembly.

FIG. 51 is a cross-sectional view of an upper mold assembly of thethermal cycle molding module showing a cam system thereof.

FIGS. 52–54 are cross-sectional view of the upper mold assembly and thecenter mold assembly of the thermal cycle molding module.

FIGS. 55 and 56 illustrate one embodiment of a temperature controlsystem for the thermal cycle molding module.

FIGS. 57–59 depict another embodiment of a temperature control systemfor the thermal cycle molding module.

FIGS. 60A–64 show a preferred embodiment of the temperature controlsystem for the thermal cycle molding module.

FIGS. 65–67 illustrate a rotary pinch valve system suitable for use inthe temperature control system of the thermal cycle molding module.

FIG. 68 is a top view of a transfer device according to the invention.

FIG. 69 is a cross-section taken along line 69—69 of FIG. 68.

FIGS. 70–74 illustrate a preferred embodiment of a transfer unit of atransfer device according to the invention.

FIG. 75 is a cross-section taken along line 75—75 of FIG. 68.

FIG. 76 shows a transfer device according to the invention transferringan insert from a thermal setting molding module to a compression module.

FIG. 77 is a top view of a rotational transfer device according to theinvention.

FIG. 78 is cross-sectional view of a rotational transfer deviceaccording to the invention.

FIG. 79 depicts transfer of compressed dosage forms from a compressionmodule to a thermal cycle molding module via a rotational transferdevice according to the invention.

FIG. 80 is a further cross-sectional view of a rotational transferdevice according to the invention.

FIGS. 81A–G illustrate operation of a rotational transfer deviceaccording to the invention, FIGS. 81E, 81F, and 81G being rear views ofFIGS. 81B, 81C, and 81D, respectively.

FIG. 82 is a side view of a thermal setting molding module according tothe invention.

FIG. 82A is a cross-section taken along line A—A of FIG. 82.

FIG. 83 is a front view of a thermal setting molding module according tothe invention.

FIG. 84 is another front view of a thermal setting molding moduleaccording to the invention.

FIGS. 85A–D illustrate operation of the thermal setting molding module.

FIG. 86 is a cross-sectional view of a preferred thermal setting moldingmodule according to the invention.

FIGS. 87 and 88 illustrate ejection of an insert from a thermal settingmolding module.

FIG. 89 depicts a dosage form having a coating thereon.

DESCRIPTION OF PREFERRED EMBODIMENTS Overview

The methods, systems, and apparatuses of this invention can be used tomanufacture conventional dosage forms, having a variety of shapes andsizes, as well as novel dosage forms that could not have beenmanufactured heretofore using conventional systems and methods. In itsmost general sense, the invention provides: 1) a compression module formaking compressed dosage forms from compressible powders, 2) a thermalcycle molding module for making molded dosage forms, or for applying acoating to a substrate, 3) a thermal setting molding module for makingmolded dosage forms, which may take the form of inserts for dosageforms, 4) a transfer device for transferring dosage forms from onemodule to another, and 5) a process for making dosage forms comprisingat least two of the above modules linked together, preferably via thetransfer device. Such process may be run on a continuous or indexingbasis.

FIG. 2 is a flow chart illustrating a preferred method for producingcertain dosage forms according to the invention, which employs all ofthe operating modules linked into a continuous process. In particular,the method reflected in FIG. 2 produces a dosage form 10 comprising amolded coating 18 on the outside surface of a compressed dosage form 12also containing an insert 14 as shown in FIG. 1A. FIGS. 3 and 4 depict apreferred system for practicing the method illustrated in FIG. 2. FIG.1B illustrates an alternative dosage form 10′ that may be made accordingto the invention comprising a molded coating 18′ over a compresseddosage form 12′. It may be appreciated from FIG. 1B that the coating andthe compressed dosage form need not have the same shape.

By way of overview, this preferred system 20 comprises a compressionmodule 100, a thermal cycle molding module 200 and a transfer device 300for transferring a compressed dosage form made in the compression module100 to the thermal cycle molding module 200 as shown in FIGS. 3 and 4.Linkage of the compression module, transfer device, and the thermalcycle molding module in this manner results in a continuous,multi-station system. Compression is accomplished in the first module,molding of a coating around the resulting compressed dosage form isperformed in the second module, and transfer of the dosage form from onemodule to the other is accomplished by the transfer device.

In other preferred embodiments, the system 20 also includes a thermalsetting molding module 400 for forming a molded dosage form, which maycomprise the final dosage form or be an insert for incorporation intoanother dosage form. In a preferred embodiment, the insert comprises ahigh potency additive. The invention is not limited to the type ornature of insert. Rather, the term insert is used simply to denote apellet-type component embedded in another dosage form. Such an insertmay itself contain a medicant, and retains its shape while being placedwithin the powder.

When used in the preferred, linked system comprising a compressionmodule, the insert is formed in Step B of FIG. 2. Following this, theinsert is inserted into uncompressed powder within compression module100. After insertion the powder and insert are compressed (Step C ofFIG. 2). The thermal setting molding module 400 can be separate from orpart of the compression module 100. If the thermal setting moldingmodule is separate from the compression module 100, a transfer device700 can be used to transfer the insert from the thermal setting moldingmodule 400 to the compression module 100.

The linked system for creating dosage forms, as well as each individualoperating module, provide many processing advantages. The operatingmodules may be used separately or together, in different sequences,depending on the nature of the dosage form desired. Two or more of thesame operating modules may be used in a single process. And although theapparatuses, methods and systems of this invention are described withrespect to making dosage forms, it will be appreciated that they can beused to produce non-medicinal products as well. For example, they may beused to make confections or placebos. The molding module can be usedwith numerous natural and synthetic materials with or without thepresence of a medicant. Similarly, the compression module can be usedwith various powders with or without drug. These examples are providedby way of illustration and not by limitation, and it will be appreciatedthat the inventions described herein have numerous other applications.

When linked in a continuous process, the operating modules can each bepowered individually or jointly. In the preferred embodiment shown inFIGS. 3 and 4, a single motor 50 powers the compression module 100, thethermal cycle molding module 200, and the transfer device 300. The motor50 can be coupled to the compression module 100, the thermal cyclemolding module 200 and the transfer device 300 by any conventional drivetrain, such as one comprising gears, gear boxes, line shafts, pulleys,and/or belts. Of course, such a motor or motors can be used to powerother equipment in the process, such as the dryer 500 and the like.

Compression Module

FIGS. 5–25 generally depict the compression module 100. FIG. 5 depicts athree dimensional view of the compression module 100 and the transferdevice 300. The compression module 100 is a rotary device that performsthe following functions: feeding powder to a cavity, compacting thepowder into a compressed dosage form and then ejecting the compresseddosage form. When the compression module is used in conjunction with thethermal cycle molding module 200, upon ejection from the compressionmodule the compressed dosage form may be transferred to the moldingmodule either directly or through the use of a transfer device, such astransfer device 300 described below. Optionally, an insert formed byanother apparatus, such as the thermal setting molding module 400described below, can be inserted into the powder in the compressionmodule before the powder is compressed into the compressed dosage form.

In order to accomplish these functions the compression module 100preferably has a plurality of zones or stations, as shown schematicallyin FIG. 6, including a fill zone 102, an insertion zone 104, acompression zone 106, an ejection zone 108 and a purge zone 110. Thus,within a single rotation of the compression module 100 each of thesefunctions are accomplished and further rotation of the compressionmodule 100 repeats the cycle.

As shown generally in FIGS. 4, 5, 9 and 14, the rotary portion of thecompression module generally includes an upper rotor 112, a circular dietable 114, a lower rotor 116, a plurality of upper 118 and lower 120punches, an upper cam 122, a lower cam 123 and a plurality of dies 124.FIG. 9 depicts a portion of the rotors 112, 116, and die table 114 froma side view, while FIG. 14 depicts a vertical cross-section through therotors 112, 116 and die table 114. FIG. 16 depicts an annularcross-section through rotors 112, 116 and die table 114. FIGS. 7 and 8are two dimensional representations of the circular path the punches118, 120 follow as they rotate with respect to the cams 122, 123 withthe rotors removed from the drawing for purposes of illustration. Theupper rotor 112, die table 114 and lower rotor 116 are rotatably mountedabout a common shaft 101 shown in FIG. 3.

Each of the rotors 112, 116 and the die table 114 include a plurality ofcavities 126 which are disposed along the circumferences of the rotorsand die table. Preferably, there are two circular rows of cavities 126on each rotor, as shown in FIG. 6. Although FIG. 6 only shows the dietable 114, it will be appreciated that the upper 112 and lower rotors116 each have the same number of cavities 126. The cavities 126 of eachrotor are aligned with a cavity 126 in each of the other rotors and thedie table. There are likewise preferably two circular rows of upperpunches 118 and two circular rows of lower punches 120, as bestunderstood with reference to FIGS. 4, 5, 9 and 14. FIG. 7 depicts theouter row of punches, and FIG. 8 illustrates the inner row of punches.

Conventional rotary tablet presses are of a single row design andcontain one powder feed zone, one compression zone and one ejectionzone. This is generally referred to as a single sided press sincetablets are ejected from one side thereof. Presses offering a higheroutput version of the single row tablet press employing two powder feedzones, two tablet compression zones and two tablet ejection zones arecommercially available. These presses are typically twice the diameterof the single sided version, have more punches and dies, and ejecttablets from two sides thereof. They are referred to as double sidedpresses.

In a preferred embodiment of the invention the compression moduledescribed herein is constructed with two concentric rows of punches anddies. This double row construction provides for an output equivalent totwo single side presses, yet fits into a small, compact space roughlyequal to the space occupied by one conventional single sided press. Thisalso provides a simplified construction by using a single fill zone 102,a single compression zone 106, and a single ejection zone 108. A singleejection zone 108 is particularly advantageous in the linked process ofthe invention, because the complexity of multiple transfer devices 300,700 having double sided construction is avoided. Of course, acompression module with one row or more than two rows can also beconstructed.

The upper punches 118 illustrated in FIGS. 7–9 extend from above thecavities 126 in the upper rotor 112 through the cavities 126 in theupper rotor and, depending on their position, either proximal to orwithin the cavities 126 of the die table 114. Similarly, the lowerpunches extend from beneath the cavities 126 in the lower rotor 116 andinto the cavities 126 in the die table 114, as is also best understoodwith reference to FIGS. 7–9. The cavities 148 in the upper and lowerrotors serve as guides for the upper 118 and lower 120 punchesrespectively.

Disposed within each of the cavities 126 of the die table is a die 124.FIGS. 9–14 depict the dies 124 and cross sections through the die table114. FIG. 9 is a partial cross section of the die table 114 taken alongan arc through a portion of the die table 114. FIG. 14 is a crosssection taken vertically along a radius though the die table 114.Because there are preferably two circular rows of dies, the two rows ofdies lie along two concentric radii, as best understood with referenceto FIGS. 6 and 14.

Preferably, the dies 124 are metallic, but any suitable material willsuffice. Each die 124 may be retained by any of a variety of fasteningtechniques within the respective cavity 126 of the die table 114. Forexample, the dies 124 may be shaped so as to have a flange 128 thatrests on a seating surface 130 formed in the die table 114 and a pair ofo-rings 144 and grooves 146, as best understood with reference to FIG.10. FIG. 10 is an enlarged view of the dies shown in FIG. 9 without theupper punches inserted into the dies. It will be appreciated that allthe dies 124 are similar in construction.

Each die 124 comprises a die cavity 132 for receiving the upper andlower punches 118, 120. The die cavities 132 and the lower punches 118that extend a distance into the die cavities 132 define the volume ofpowder to be formed into the compressed dosage form and hence the dosageamount. Thus, the size of die cavity 132 and the degree of insertion ofthe punches into the die cavities 132 can be appropriately selected oradjusted to obtain the proper dosage.

In a preferred embodiment, the die cavities are filled using theassistance of a vacuum. Specifically, each die 124 has at least one port134 disposed within it, as shown in FIGS. 10, 11, and 12. Disposedwithin or proximal to each port 134 is a filter 136. The filters 136 aregenerally a metallic mesh or screen appropriately sized for theparticles that will be flowing through the die cavities 134. Onesurprising feature of the present compression module is that the filtersmay comprise screens having a mesh size larger than the average particlesize of the powder, which is typically about 50 to about 300 microns.While the filters 136 are preferably metallic, other suitable materialsmay be employed, such as fabrics, porous metals or porous polymerconstructions. The filter 136 may be a single stage or multi-stagefilter, but in the preferred embodiment the filter 136 is a single stagefilter. The filter may also be located anywhere in the vacuum passages.Alternatively, it can be located externally to the die table as shown inFIG. 12A. In a preferred embodiment the filters are located in the diewall ports 134 as close as possible to the punches. See FIG. 12. Thiscreates the least amount of residue requiring purging and subsequentrecycling in the purge zone 110 and powder recovery system. The top ofthe die cavity 132 is preferably open and defines a second port.

The die table 114 preferably comprises channels 138 within it thatcircle each pair of dies 124 and extend to the ports 134, as best shownin FIG. 11. In addition the die table 114 preferably has a plurality ofrelatively small openings 140 on its outer periphery that connect eachof the respective channels 138, so that the die cavities can beconnected to a vacuum source (or suction source). Disposed along aportion of the periphery of the die table 114 are a stationary vacuumpump 158 and a vacuum manifold 160, which make up a portion of the fillzone 102, as shown in FIG. 14. The vacuum pump 158 provides a source ofvacuum for pulling powder into the die cavities 132. The vacuum pump 158is connected to the vacuum manifold 160 with suitable tubing 162. Thevacuum manifold 160 is aligned with the openings 140. As the die table114 rotates during operation of the vacuum pump 158, the openings 140 inthe die table 114 become aligned with the vacuum manifold 160 and avacuum is formed through the respective channel 138 and die cavity 132.

Vacuum is accordingly applied through the respective ports 134 andchannels 138 to pull powder into the die cavity 132. See FIGS. 20 and21. A seal can be created around the ports 134 and the channel 138proximal to the port 134 with any of a variety of techniques. In thepreferred embodiment shown a seal is created using o-rings 144 andgrooves 146.

Conventional tablet presses rely on highly flowable powders and theeffects of gravity to fill the die cavity. The performance of thesemachines in terms of fill accuracy and press speed are thereforeentirely dependent on the quality and flowabilty of the powder. Sincenon-flowing and poorly flowing powders cannot be effectively run onthese machines these materials must be wet granulated in a separatebatch process which is costly, time consuming, and energy inefficient.

The preferred vacuum fill system described is advantageous overconventional systems in that poorly flowing and non-flowing powders canbe run at high speed and high accuracy without the need for wetgranulation. In particular, powders having a minimum orifice diameter offlowability greater than about 10, preferably 15, more preferably 25 mm,as measured by the Flowdex test, may be successfully compressed intodosage forms in the present compression module. The Flowdex test isperformed as follows. The minimum orifice diameter is determined using aFlodex Apparatus Model 21-101-050 (Hanson Research Corp., Chatsworth,Calif.), which consists of a cylindrical cup for holding the powdersample (diameter 5.7 cm, height 7.2 cm), and a set of interchangeabledisks, each with a different diameter round opening at the center. Thedisks are attached to the cylindrical cup to form the bottom of the“cup.” For filling, the orifice is covered with a clamp. Minimum orificediameter measurements are performed using 100 g samples of powder. A 100g sample is placed into the cup. After 30 seconds the clamp is removed,and the powder allowed to flow out of the cup through the orifice. Thisprocedure is repeated with increasingly smaller orifice diameters untilthe powder no longer flows freely through the orifice. The minimumorifice diameter is defined as the smallest opening through which thepowder flows freely.

Moreover, compression of such relatively poorly flowing powders may bedone while operating the compression module at high speeds, i.e., thelinear velocity of the dies is typically at least about 115 cm/sec,preferably at least about 230 cm/sec. In addition, weight variations inthe final compressed dosage forms are significantly less, since vacuumfilling of the die cavity causes a densifying effect on the powder inthe die cavity. This minimizes the density variations powders typicallyexhibit due to compaction, static head pressure variation, or lack ofblend homogeneity. The relative standard deviation in weight ofcompressed dosage forms made according to the invention is typicallyless than about 2%, preferably less than about 1%.

In addition, better content uniformity can also be achieved with thepresent vacuum fill system, since little mechanical agitation isrequired to cause the powder to flow into the die cavity. Inconventional tablet presses, the mechanical agitation required to assuredie filling has the adverse effect of segregating small from largeparticles.

Known powder filling equipment employ vacuum to fill uncompressedpowders into capsules or other containers. See. For example, Aronson,U.S. Pat. No. 3,656,518 assigned to Perry Industries, Inc. However,these systems have filters that are always in contact with the powderand therefore unsuitable for adaptation to compression machines. Forceson the order of 100 kN can be experienced during compression of powdersinto dosage forms. Such high forces would damage the filters. U.S. Pat.No. 4,292,017 and U.S. Pat. No. 4,392,493 to Doepel describe a highspeed rotary tablet compression machine which uses vacuum die filling.However separate turntables are used for filling and compression. Diesare filled on the first turntable and thereafter transferred to aseparate turntable for compression. Advantageously, according to theinvention, the filters are protected during compression, since the lowerpunches move above the filter port prior to the die cavities enteringthe compression zone.

Powder is fed into the die cavities 132 in the fill zone 102. The powdermay preferably consist of a medicant optionally containing variousexcipients, such as binders, disintegrants, lubricants, fillers and thelike, as is conventional, or other particulate material of a medicinalor non-medicinal nature, such as inactive placebo blends for tableting,confectionery blends, and the like. One particularly preferredformulation comprises medicant, powdered wax (such as shellac wax,microcrystalline wax, polyethylene glycol, and the like), and optionallydisintegrants and lubricants and is described in more detail in commonlyassigned co-pending U.S. patent application Ser. No. 09/966,493, filedon Sep. 28, 2001, entitled “Immediate Release Tablet” and published asUS 2003-0068373 A1 which is hereby incorporated by reference.

Suitable medicants include for example pharmaceuticals, minerals,vitamins and other nutraceuticals. Suitable pharmaceuticals includeanalgesics, decongestants, expectorants, antitussives, antihistamines,gastrointestinal agents, diuretics, bronchodilators, sleep-inducingagents and mixtures thereof. Preferred pharmaceuticals includeacetaminophen, ibuprofen, flurbiprofen, ketoprofen, naproxen,diclofenac, aspirin, pseudoephedrine, phenylpropanolamine,chlorpheniramine maleate, dextromethorphan, diphenhydramine, famotidine,loperamide, ranitidine, cimetidine, astemizole, terfenadine,fexofenadine, loratadine, cetirizine, antacids, mixtures thereof andpharmaceutically acceptable salts thereof. More preferably, the medicantis selected from the group consisting of acetaminophen, ibuprofen,pseudoephedrine, dextromethorphan, diphenhydramine, chlorpheniramine,calcium carbonate, magnesium hydroxide, magnesium carbonate, magnesiumoxide, aluminum hydroxide, mixtures thereof, and pharmaceuticallyacceptable salts thereof.

The medicant(s) is present in the dosage form in a therapeuticallyeffective amount, which is an amount that produces the desiredtherapeutic response upon oral administration and can be readilydetermined by one skilled in the art. In determining such amounts, theparticular medicant being administered, the bioavailabilitycharacteristics of the medicant, the dose regime, the age and weight ofthe patient, and other factors must be considered, as known in the art.Preferably, the compressed dosage form comprises at least about 85weight percent of medicant.

If the medicant has an objectionable taste, and the dosage form isintended to be chewed or disintegrated in the mouth prior to swallowing,the medicant may be coated with a taste masking coating, as known in theart. Examples of suitable taste masking coatings are described in U.S.Pat. No. 4,851,226, U.S. Pat. No. 5,075,114, and U.S. Pat. No.5,489,436. Commercially available taste masked medicants may also beemployed. For example, acetaminophen particles which are encapsulatedwith ethylcellulose or other polymers by a coaccervation process may beused in the present invention. Coaccervation-encapsulated acetaminophenmay be purchased commercially from Eurand America, Inc. Vandalia, Ohio,or from Circa Inc., Dayton, Ohio.

Suitable excipients include fillers, which include water-solublecompressible carbohydrates such as dextrose, sucrose, mannitol,sorbitol, maltitol, xylitol, lactose, and mixtures thereof, waterinsoluble plasticly deforming materials such as microcrystallinecellulose or other cellulosic derivatives, water-insoluble brittlefracture materials such as dicalcium phosphate, tricalcium phosphate,and the like; other conventional dry binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose, and the like; sweeteners suchas aspartame, acesulfame potassium, sucralose, and saccharin;lubricants, such as magnesium stearate, stearic acid, talc, and waxes;and glidants, such as colloidal silicon dioxide. The mixture may alsoincorporate pharmaceutically acceptable adjuvants, including, forexample, preservatives, flavors, antioxidants, surfactants, and coloringagents. Preferably however, the powder is substantially free of watersoluble polymeric binders and hydrated polymers.

Included within the fill zone 102 may be a doctor blade 131 as shown inFIG. 9 that “doctors” or levels the powder along the die table 114 asthe die table 114 rotates through the fill zone 102. In particular, as afilled die cavity 132 rotates past the powder bed, the die table 114passes against the doctor blade 131 (as shown in FIG. 9) which scrapesthe surface of the die table 114 to assure the precise leveling andmeasurement of powder filling the die cavity 132.

After the punches leave the fill zone 102 they enter the insertion zone104. In this zone the lower punches 120 may retract slightly to allowfor an optional insert to be embedded into the soft uncompressed powderin the die cavity 132 via a transfer device 700. This mechanism isdescribed in greater detail below.

After continued rotation and before entering the compression zone 106,the upper punch 118 is pushed into the die cavity 132 by the cam track122 as shown in FIGS. 7, 8 and 16. Following this, the upper and lowerpunches 118, 120 engage the first stage rollers 180 as shown in FIG. 16where force is applied to the powder via the first stage rollers. Afterthis initial compression event, the punches enter the second stagerollers 182 as shown in FIG. 16. The second stage rollers 182 drive thepunches 118, 120 into the die cavity 132 to further compress the powderinto the desired compressed dosage form. Once past the compression zonethe upper punches retract from the die cavity 132 and the lower punchesbegin to move upward prior to entering the ejection zone 108.

Because the distances traveled by the outer and inner rows of punchesalong their respective circular paths differ, the sizes of the rollers180 and 182 that activate each row differ. This enables compression ofthe inner and outer rows to be simultaneous. In particular, the rollersthat activate the inner row are smaller in diameter than the rollersthat activate the outer row (as shown in FIG. 15), but the inner andouter rollers have their greatest diameter along the same radial line.Thus, the outer row punches and inner row punches will each begin to becompressed at the same time, thus entering the die cavitiessimultaneously. By assuring the same dwell time under compression,consistency of compressed dosage form thickness between inner and outerrows is assured. This thickness control is particularly important shouldthe compressed dosage forms be subjected to subsequent operations, suchas the application of coatings and the like.

FIGS. 17, 18, and 19 are three possible geometries for the compressionframe on which the compression rollers are mounted. FIG. 17 illustratesone possible “C” geometry for the compression frame. As shown in FIGS.17B and 17C deflection of the compression frame displaces the rollers bythe amount “Δ” under the significant forces of compression (The doublerow compression module illustrated here preferably has twice this ratingor 200 kN.) An advantage of the frame geometry depicted in FIGS. 17Athrough 17C is that the displacement Δ is parallel to the radial axis ofthe compression rollers 182. This slight deflection can easily becompensated for by thickness controls on the machine. However, as shownin FIG. 17A, the frame occupies a significant amount of space.Accordingly there is less room for other equipment to be mounted on ornear the compression module (this is represented by angle φ).

FIGS. 18A through 18C illustrate an alternate “C” frame geometry. Thisarrangement has the advantage of occupying significantly less space thanthe arrangement outlined in FIGS. 17A through 17C. However in thisembodiment, deflection of the compression frame displaces the rollersout of the horizontal plane. This is represented by angle θ in FIG. 18C.θ increases as the load increases. The net effect is an inconsistencybetween inner and outer row compressed dosage form thickness that alsovaries with compression force.

FIGS. 19A through 19D illustrate a preferred embodiment of thecompression frame. As shown in FIG. 19D, the frame comprises a throat179 and two arms 178. The arms 178 forms an oblique angle Ω with respectto the axial axis of the rollers A—A. As shown in FIGS. 19B and 19Ddespite deflection of the frame anhd displacement Δ of the rollers, therollers remain horizontal. An additional advantage of this constructionis a significantly greater free space angle φ, as shown in FIG. 19A.This compression frame configuration can also advantageously pivot aboutan axis away from the compression module to allow for access or removalof the die table.

Following the formation of the compressed dosage form in the compressionzone 106, the respective die cavity 132 rotates to ejection zone 108 asshown in FIG. 6. The upper punches 118 move upward due to the slope ofthe cam tracks 122 as shown in FIGS. 7, 8, and 16 and out of the diecavities. The lower punches 120 move upward and into the die cavities132 until eventually the lower punches 120 eject the compressed dosageform out of the die cavity 132, and optionally into a transfer device300 as shown in FIG. 6.

In the purge zone 110, excess powder is removed from the filters 136after the compressed dosage form has been ejected from the die cavities132. This cleans the filters before the next filling operation. Thepurge zone 110 accomplishes this by blowing air through or placingsuction pressure on the filters 136 and channels 138.

In a preferred embodiment the purge zone 110 includes a stationarypositive pressure source 190, such as an air pump or pressurized airbank, and a pressure manifold 192, as shown schematically in FIG. 12.The pressure manifold 192 may be disposed proximal to the periphery ofthe die table 114 and between the compression zone 106 and the fill zone102, as best understood with reference to FIGS. 20 and 22. The pressuremanifold 192 preferably has at least one port 194 (although any numberof ports can be used) that can be placed in fluid communication with thefilters as the die table 114 rotates. Pressure source 190 appliespressure through tubing 196 and the pressure manifold 192 to eachrespective channel 138 and die cavity 132 as the die table 114 rotatesand the openings 140 become aligned with the pressure manifold ports194, as shown in FIGS. 20 and 22. It will be appreciated from FIGS. 7and 8 that in the purge zone 110 the upper punches 118 are removed fromthe die cavities 132 and the lower punches 120 are disposed beneath thefilters 136, so that pressure can be applied through the openings 140 asshown in FIG. 22. When the lower punch 120 is inserted into the diecavity 132 above the filters 136 and die ports 134, die cavity 132 isdisconnected from the vacuum source 142, and vacuum is no longer exertedon the powder.

The positive pressure cleans out the filters to remove any buildup ofpowder by transmitting pressurized air from the pressure manifoldthrough the channels and through the die cavities. The pressurized airblows the powder up through the top of the die cavities to a collectionmanifold 193, shown in FIGS. 22, 24 and 25. From the collectionmanifold, the powder can be sent to a collection chamber or the like andif desired reused.

In order to increase the efficiency of the purge zone 110, the purgezone 110 may further include a suction source 197 that applies suctionto the collection manifold 193 as shown in FIG. 22 and a collectionchamber 193 that receives the powder from the suction source 197.

If desired the purge zone 110 can include a recovery system to recoverthe removed powder and send it back to hopper 169 or the powder bed 171.This is advantageous because it minimizes waste. One embodiment of therecovery system is depicted in FIGS. 23 and 24. The recovery systemfeeds the purged powder into the die cavities 132 prior to their arrivalat the fill zone 102. In this embodiment, the recovery system includesshoe block 195, a blower 197, a cyclone receiver 199, a deliverymanifold 198, and an agitator 191. The shoe block 195 is disposed aboutand contacts a portion of the periphery of the die table 114 between thepressure manifold 192 and the fill zone 102 as shown in FIG. 23. Theshoe block 195 may be spring loaded by springs 189 so that it fitstightly against the die table 114 as the die table 114 rotates past it.The shoe block 195 is aligned with the openings 140 in the die table 114to create a pressure seal between the openings 140 and the shoe block189. This pressure seal prevents purged powder in the die cavities 132from being blown back out of the die cavities. Alternately, shoe block195 can be dispensed with if the lower punches 120 are moved upward tocover the die ports 134 and then moved down again prior to entering thefill zone 102.

The blower 197 shown in FIG. 24 is coupled to the collection manifold193 to pull powder from the die cavities 132. The blower 197 sendspurged powder from the collection manifold 193 to the cyclone dustseparator 199, which operates at a partial vacuum. The cyclone dustseparator 199 collects the purged powder and sends it to the deliverymanifold 198 as shown in FIG. 24. A filter bag dust separator can besubstituted for the cyclone dust separator. Once the dust is separatedfrom the air stream 199 it falls into the delivery manifold 198, asshown in FIG. 24

The delivery manifold 198 is disposed just above the die table 114 sothat as the die table 114 rotates, the top of the die table 114 comesinto contact with the delivery manifold 198, creating a pressure sealbetween the delivery manifold 198 and the die table 114. The diecavities are open to the delivery manifold 198 as shown in FIG. 24 sothat purged powder can flow into the die cavities by gravity or othermeans such as an optional vacuum source (not shown). The agitator 191rotates within the delivery manifold 198 to direct the purged powder tothe die cavities 132.

In operation, the die table 114 rotates proximal to the pressuremanifold 192 and beneath the collection manifold 193. As describedabove, pressurized air is sent through the openings 140 in the peripheryof the die table and vacuum is applied to the collection manifold 193and the two together cause powder to flow from the channels 138 and thedie cavities 132 as shown in FIG. 24 to the collection manifold 193.

From the collection manifold 193, the purged powder flows to the cyclonedust separator 199 where the purged powder is directed to the agitator191 and the delivery manifold 198. The die table 114 continues to rotateso that the purged die cavities 132 pass to the shoe block 195 as shownin FIG. 23. The openings 140 of the die cavities are sealed by the shoeblock 195 so that powder can flow into the die cavities 132, but willnot flow out of the openings 140. The delivery manifold 198 directs thepurged powder from the cyclone dust separator 199 back into the diecavities 132. Following this, the die table 114 continues to rotate tothe fill zone 102.

An alternate embodiment of the powder recovery system is shown in FIG.25. This embodiment dispenses with the delivery manifold 198 and shoeblock 195. Purged powder is delivered back into the fill zone 102 ratherthan into the die cavity 134. A rotary valve 125 is employed to preventpowder from powder bed 171 from entering the cyclone dust separator 199.A series of two gate or flap valves (not shown) may also be used inplace of the rotary valve 125.

The above systems for purging the powder from the die cavities 132 andchannels 138 prevents powder build-up and minimizes waste. Of course,this invention in its broadest sense can be practiced without such apurge zone 110 or a recovery system.

Thermal Cycle Molding Module

The thermal cycle molding module 200 may function in one of severaldifferent ways. It may for example be used to form a shell or coatingover at least part of a dosage form such as a compressed dosage formsuch as a tablet. It may also be used as stand alone equipment toproduce a molded dosage form per se. Such a coating or dosage form ismade from a flowable material. Preferably, the molding module is used toapply a coating of flowable material to a dosage form. More preferably,the molding module is used to apply a coating of a flowable material toa compressed dosage form made in a compression module of the inventionand transferred via a transfer device also according to the invention.The coating is formed within the molding module by injecting theflowable material, preferably comprising a natural or synthetic polymer,into a mold assembly around the dosage form. The flowable material mayor may not comprise a medicant and appropriate excipients, as desired.Alternately, the molding module may be used to apply a coating offlowable material to a molded dosage form, or other substrate.

Advantageously, the thermal cycle molding module may be used to applysmooth coatings to substrates that are irregular in topography. Thecoating thickness achieved with the thermal cycle molding moduletypically ranges from about 100 to about 400 microns. However, therelative standard deviation in the thickness of the coating can be ashigh as about 30%. This means the outside of the coated dosage form canbe made to be highly regular and smooth, even if the substrate below itis not. Once coated, the relative standard deviations in thickness anddiameter of the coated dosage form are typically not greater than about0.35%. Typical coated dosage form thicknesses (shown in FIG. 89 as t)are on the order of about 4 to 10 mm, while typical coated dosage formdiameters (d in FIG. 89) range from about 5 to about 15 mm. It should benoted that subcoats, which are often present in conventional dosageforms, are not necessary on dosage forms coated using the thermal cyclemolding module.

The thermal cycle molding module 200 preferably cycles between hot andcold temperatures during operation. Preferably, the actual mold cavityis held at a temperature generally above the melting point or gel pointof the flowable material during injection and filling thereof. After themold cavity is filled its is quickly decreased to below the meltingpoint or gel point of the flowable material thus causing it to solidifyor set. The mold itself is thin like an “egg shell,” and constructed ofa material with a high thermal conductivity, such that the mass andgeometry of the mold have a negligible effect on the speed at which thisthermal cycle is accomplished.

A significant advantage, then, of the thermal cycle molding module isthe dramatically reduced cycle times it affords due to the fact that itcan cycle between temperatures that are relatively far apart. Thetemperature differential between the actual mold cavity and the flowablematerial is the major driving force in the solidification rate of theflowable material. By substantially increasing this rate higherequipment output can be achieved and subsequent savings in equipment,labor, and plant infrastructure can be realized.

Moreover, molding of gelatin or similar materials, for examplenon-polymers such as the basic elements, metals, water, and alcohol,have not previously been possible using conventional molding techniquessuch as injection molding. Precise control over the temperature andpressure of such materials, as well as the mold cavity temperature arerequired to assure these materials are sufficiently flowable to fill themold cavity completely. On the other hand, the mold cavity mustsubsequently be cooled enough to assure that the material willeventually solidify. In particular, gelatin, once hydrated, has a veryabrupt transition temperature between the liquid phase and the solid orgel phase. It therefore cannot be characterized as a thermoplasticmaterial. Accordingly, in order to mold gelatin and materials like itthe temperature of the mold must cycle from a first temperature aboveits melting or gel point (to assure that the material will flow andcompletely fill the mold cavity) to a second temperature below itsmelting or gel point (to solidify it).

In a preferred embodiment of the invention, the flowable materialcomprises gelatin. Gelatin is a natural, thermogelling polymer. It is atasteless and colorless mixture of derived proteins of the albuminousclass which is ordinarily soluble in warm water. Two types ofgelatin—Type A and Type B—are commonly used. Type A gelatin is aderivative of acid-treated raw materials. Type B gelatin is a derivativeof alkali-treated raw materials. The moisture content of gelatin, aswell as its Bloom strength, composition and original gelatin processingconditions, determine its transition temperature between liquid andsolid. Bloom is a standard measure of the strength of a gelatin gel, andis roughly correlated with molecular weight. Bloom is defined as theweight in grams required to move a half-inch diameter plastic plunger 4mm into a 6.67% gelatin gel that has been held at 10° C. for 17 hours.

In a preferred embodiment wherein the flowable material is an aqueoussolution comprising 20% 275 Bloom pork skin gelatin, 20% 250 Bloom BoneGelatin, and approximately 60% water, the mold cavities are cycledbetween about 35° C., and about 20° C. in about 2 seconds (a total of 4seconds per cycle).

Other preferred flowable materials comprise polymeric substances such aspolysaccharides, cellulosics, proteins, low and high molecular weightpolyethylene glycol (including polyethylene oxide), and methacrylic acidand methacrylate ester copolymers. Alternative flowable materialsinclude sucrose-fatty acid esters; fats such as cocoa butter,hydrogenated vegetable oil such as palm kernel oil, cottonseed oil,sunflower oil, and soybean oil; mono- di- and triglycerides,phospholipids, waxes such as Carnauba wax, spermaceti wax, beeswax,candelilla wax, shellac wax, microcrystalline wax, and paraffin wax;fat-containing mixtures such as chocolate; sugar in the form on anamorphous glass such as that used to make hard candy forms, sugar in asupersaturated solution such as that used to make fondant forms;carbohydrates such as sugar-alcohols (for example, sorbitol, maltitol,mannitol, xylitol), or thermoplastic starch; and low-moisture polymersolutions such as mixtures of gelatin and other hydrocolloids at watercontents up to about 30%, such as for example those used to make “gummi”confection forms.

The flowable material may optionally comprise adjuvants or excipients,in which may comprise up to about 20% by weight of the flowablematerial. Examples of suitable adjuvants or excipients includeplasticizers, detackifiers, humectants, surfactants, anti-foamingagents, colorants, flavorants, sweeteners, opacifiers, and the like. Inone preferred embodiment, the flowable material comprises less than 5%humectants, or alternately is substantially free of humectants, such asglycerin, sorbitol, maltitol, xylitol, or propylene glycol. Humectantshave traditionally been included in pre-formed films employed inenrobing processes, such as that disclosed in U.S. Pat. No. 5,146,730and U.S. Pat. No. 5,459,983, assigned to Banner Gelatin Products Corp.,in order to ensure adequate flexibility or plasticity and bondability ofthe film during processing. Humectants function by binding water andretaining it in the film. Pre-formed films used in enrobing processescan typically comprise up to 45% water. Disadvantageously, the presenceof humectant prolongs the drying process, and can adversely affect thestability of the finished dosage form.

Advantageously, drying of the dosage form after it has left the thermalcycle molding module not is required when the moisture content of theflowable material is less than about 5%.

Whether coating a dosage form or preparing a dosage form per se, use ofthe thermal cycling molding module advantageously avoids visible defectsin the surface of the product produced. Known injection moldingprocesses utilize sprues and runners to feed moldable material into themold cavity. This results in product defects such as injector marks,sprue defects, gate defects, and the like. In conventional molds, spruesand runners must be broken off after solidification, leaving a defect atthe edge of the part, and generating scrap. In conventional hot runnermolds, sprues are eliminated, however a defect is produced at theinjection point since the hot runner nozzle must momentarily contact thechilled mold cavity during injection. As the tip of the nozzle retractsit pulls a “tail” with it, which must be broken off. This defect isparticularly objectionable with stringy or sticky materials. Unwanteddefects of this nature would be particularly disadvantageous forswallowable dosage forms, not only from a cosmetic standpoint butfunctionally as well. The sharp and jagged edges would irritate orscratch the mouth, tongue and throat.

The thermal cycle molding module avoids these problems. It employsnozzle systems (referred to herein as valve assemblies) each comprisinga valve body, valve stem and valve body tip. After injection of flowablematerial into the mold cavity, the valve body tip closes the mold cavitywhile comforming seemlessly to the shape of the mold cavity. Thistechnique eliminates visible defects in the molded product and alsoallows a wide range of heretofore unmoldable or difficult to moldmaterials to be used. Moreover, use of the thermal cycle molding moduleaccording to the invention avoids the production of scrap flowablematerial, in that substantially all of the flowable material becomespart of the finished product.

For convenience, the thermal cycle molding module is described generallyherein as it is used to apply a coating to a compressed dosage form.However, FIG. 26A, which is explained further below, depicts anembodiment in which molded dosage forms per se are made using thethermal cycle molding module.

The thermal cycle molding module 200 generally includes a rotor 202, asshown in FIGS. 2 and 3 around which a plurality of mold units 204 aredisposed. As the rotor 202 revolves, the mold units 204 receivecompressed dosage forms, preferably from a transfer device such astransfer device 300. Next, flowable material is injected into the moldunits to coat the compressed dosage forms. After the compressed dosageforms have been coated, the coating may be further hardened or dried ifrequired. They may be hardened within the mold units or they may betransferred to another device such as a dryer. Continued revolution ofthe rotor 202 repeats the cycle for each mold unit.

FIG. 29 is a three dimensional view of the thermal cycle molding module200 as described above. FIG. 30 is a partial view through a section ofthe thermal cycle molding module as viewed from above showing multiplemold units 204. FIG. 31 is a section through one of the mold units 204.The thermal cycle molding module 200 includes at least one reservoir 206containing the flowable material, as shown in FIG. 4. There may be asingle reservoir for each mold unit, one reservoir for all the moldunits, or multiple reservoirs that serve multiple mold units. In apreferred embodiment, flowable material of two different colors are usedto make the coating, and there are two reservoirs 206, one for eachcolor. The reservoirs 206 may be mounted to the rotor 202 such that theyrotate with the rotor 202, or be stationary and connected to the rotorvia a rotary union 207 as shown in FIG. 4. The reservoirs 206 can beheated to assist the flowable material in flowing. The temperature towhich the flowable material should be heated of course depends on thenature of the flowable material. Any suitable heating means may be used,such as an electric (induction or resistance) heater or fluid heattransfer media. Any suitable tubing 208 may be used to connect thereservoirs 206 to the mold unit 204. In a preferred embodiment, tubing208 extends through each of the shafts 213 as shown in FIGS. 30 and 31to each of the center mold assemblies 212.

A preferred embodiment of a mold unit 204 is shown in FIG. 31. The moldunit 204 includes a lower retainer 210, an upper mold assembly 214, anda center mold assembly 212. Each lower retainer 210, center moldassembly 212, and upper mold assembly 214 are mounted to the rotor 202by any suitable means, including but not limited to mechanicalfasteners. Although FIG. 31 depicts a single mold unit 204 all of theother mold units 204 are similar. The lower retainer 210 and the uppermold assembly 214 are mounted so that they can move vertically withrespect to the center mold assembly 212. The center mold assembly 212 ispreferably rotatably mounted to the rotor 202 such that it may rotate180 degrees.

FIG. 26A depicts the sequence of steps for making a molded dosage formper se. This employs a simpler embodiment of the thermal cycle moldingmodule is employed in that the center mold assembly 212 need not rotate.FIG. 26B is a timing diagram showing movement of the mold units 204 asthe rotor 202 of the thermal molding module completes one revolution.FIG. 26C is a section through one of the mold units. At the beginning ofthe cycle (the rotor at the 0 degree position) the upper mold assembly214 and the center mold assembly 212 are in the open position. As therotor continues to revolve the mold assemblies close to form a moldcavity. After the mold assemblies close, hot flowable material isinjected from either the upper mold assembly, the center mold assembly,or both into the mold cavity. The temperature of the mold cavity isdecreased, and a thermal cycle is completed. After the flowable materialhardens, the mold assemblies open. Upon further revolution of the rotor,the finished molded dosage forms are ejected thus completing one fullrevolution of the rotor.

FIG. 27A depicts the sequence of steps for using a second embodiment ofthe thermal cycle molding module. Here a coating is formed over acompressed dosage form. In this embodiment, the thermal cycle moldingmodule coats the first half of a dosage form during revolution of therotor 202 between 0 and 180 degrees. The second half of the dosage formis coated during revolution of the rotor between 180 and 360 degrees.FIG. 27B is a timing diagram showing movement and rotation of the moldunits as the rotor completes one revolution. FIG. 27C is a sectionthrough one of the mold units showing upper mold assembly 214 and centermold assembly 212. Note that the center mold assembly 212 in thisembodiment is capable of rotation about its axis.

At the beginning of the molding cycle (rotor at the 0 degree position)the mold assemblies are in the open position. Center mold assembly 212has received a compressed dosage form, for example from a compressionmodule according to the invention transferred via a transfer device alsoaccording to the invention. As the rotor continues to revolve, the uppermold assembly 214 closes against center mold assembly 212. Next,flowable material is injected into the mold cavity created by union ofthe mold assemblies to apply a shell to the first half of the compresseddosage form. The flowable material is cooled in the mold cavity. Themold assemblies open with the half coated compressed dosage formsremaining in the upper mold assembly 214. Upon further revolution of therotor, the center mold assembly rotates 180 degrees. As the rotor movespast 180 degrees the mold assemblies again close and the uncoated halfof the compressed dosage form is covered with flowable material. Athermal cycle is completed with setting or hardening of the coating onthe second half of the compressed dosage form. The mold assemblies againopen and the coated compressed dosage form is ejected from the thermalcycle molding module.

FIG. 28A depicts the sequence of steps for using a preferred embodimentof the thermal cycle molding module to form a coating over a compresseddosage form. In this embodiment, part of a compressed dosage form iscoated in the mold cavity created by union of the lower retainer and thecenter mold assembly 212 during revolution of the rotor between 0 and360 degrees. Simultaneously, the remainder of a second compressed dosageform, the first part of which has already been coated during a previousrevolution of the rotor, is coated in the mold cavity created by theunion of the center mold assembly and the upper mold assembly 214.Compressed dosage forms transit through the thermal cycle molding modulein a helix, receiving partial coatings during a first full rotation ofthe rotor, and then the remainder of their coatings during a second fullrotation of the rotor. Compressed dosage forms are therefore retained inthe thermal cycle molding module for two revolutions of the rotor (720degrees) prior to being ejected as finished products. This embodiment ofthe thermal cycle molding module is advantageous in that size of themolding module may be drastically reduced, i.e., to one half thediameter of the embodiment shown in FIG. 27A for a given dosage formoutput per rotation. This embodiment of the thermal cycle molding moduleis more economic to fabricate, operate, and house in a high outputmanufacturing plant.

FIG. 28B is a timing diagram showing movement of the mold units androtation of the center mold assembly as the rotor completes tworevolutions (0 through 720 degrees). FIG. 28C is a section through oneof the mold units. At the beginning of the cycle (0 degrees rotation ofthe rotor) the mold units are in the open position. The center moldassembly 212 contains a partially coated compressed dosage form. Thelower mold assembly 210 receives an uncoated compressed dosage form, forexample from a compression module 100 via a transfer device 300. Uponrotation of the rotor, the center mold assembly 212 rotates 180 degreesabout its axis, which is radial to the rotor. This presents thepartially coated compressed dosage form to the upper mold assembly 214,which is empty. The partially coated compressed dosage form is thendisposed between the upper and center mold assemblies 212, 214. As therotor continues to rotate, the mold units close. The lower retainer 210and center mold assembly 212 create a seal around the uncoatedcompressed dosage form, as shown in FIG. 34.

Flowable material is injected into the mold cavity created between thelower retainer 210 and the center mold assembly 212 over the uncoatedcompressed dosage form to cover a part thereof. In a preferredembodiment, the flowable material coats about half of the uncoatedcompressed dosage form, the top half as shown in FIG. 34. Simultaneouslywith the mating of the lower retainer 210 and the center mold assembly212, the center 212 and upper 214 mold assemblies mate to create sealsaround the partially coated compressed dosage form. Flowable material isinjected through the upper mold assembly 214 into the mold cavitycreated by the center mold assembly and the upper mold assembly to coatthe remaining portion of the partially coated compressed dosage form,the top portion as viewed in FIG. 34. The lower retainer 210 and uppermold assembly 214 are mated with the center mold assembly 212simultaneously. Accordingly, when an uncoated compressed dosage form isbeing partially coated between the lower retainer 210 and the centermold assembly 212, the remainder of a partially coated compressed dosageform is being coated between the center 212 and upper mold assemblies214.

Following this, the lower retainer and the mold assemblies separate. Thefully coated compressed dosage form is retained in the upper moldassembly 214. The partially coated compressed dosage form is retained inthe center mold assembly 214, as shown in FIG. 35. The fully coatedcompressed dosage form is then ejected from the upper mold assembly 214as shown schematically in FIG. 35. Following this, an uncoatedcompressed dosage form is transferred to the lower retainer 210, suchthat the lower retainer 210, center mold assembly 212, and upper moldassembly 214 return to the position of FIG. 32. The process then repeatsitself.

In the preferred embodiment shown, each mold unit can coat eightcompressed dosage forms. Of course, the mold units can be constructed tocoat any number of compressed dosage forms. Additionally and preferably,the compressed dosage forms are coated with two different coloredflowable materials. Any colors can be used. Alternatively, only aportion of the compressed dosage form may be coated while the remainderis uncoated.

The molds may also be constructed to impart regular or irregular,continuous or discontinuous, coatings, i.e., of various portions andpatterns, to the dosage forms. For example, dimple patterned coatings,similar to the surface of a golf ball, can be formed using a moldingmodule comprising mold insert having dimple patterns on their surfaces.Alternatively, a circumferential portion of a dosage form can be coatedwith one flowable material and the remaining portions of the dosage formwith another flowable material. Still another example of an irregularcoating is a discontinuous coating comprising holes of uncoated portionsaround the dosage form. For example, the mold insert may have elementscovering portions of the dosage form so that such covered portions arenot coated with the flowable material. Letters or other symbols can bemolded onto the dosage form. Finally, the present molding module allowsfor precise control of coating thickness on a dosage form.

When used to form a coating on a dosage form, the molding module of thisinvention advantageously dispenses with the need for a subcoating on thedosage form. When conventional compressed dosage forms are coated byprocesses such as dipping, this generally requires placing a subcoatingon the compressed dosage form prior to the dipping step.

Preferred embodiments of the lower retainer, center mold assembly andupper mold assembly are described below. These embodiments of the lowerretainer, center mold assembly and upper mold assembly are part of athermal cycle molding module for applying a coating to a compresseddosage form.

1. The Lower Retainer

The lower retainer 210 is mounted to the rotor 202 as shown in FIG. 31in any suitable fashion and comprises a plate 216 and a dosage formholder 217. Each dosage form holder can be connected to the plate by anyone of a variety of fastening techniques including without limitationsnap rings and groves, nuts and bolts, adhesives and mechanicalfasteners. Although the cross-section of the lower retainer shown inFIGS. 32 through 35 depicts only four dosage form holders 217, the lowerretainer preferably has four additional dosage form holders for a totalof eight. Each dosage form holder includes a flanged outer sleeve 218,an elastomeric collet 220, a center support stem 222 and a plurality offlexible fingers 223.

The configuration of the lower retainer is best understood withreference to FIGS. 36–39A. The center support stem 222 establishes thevertical position of the dosage form. The elastomeric collet 220 masksand seals the periphery of the dosage form, as best illustrated in FIGS.36 and 37. Each elastomeric collet 220 mates with a correspondingportion of the center mold assembly 212 in order to create a seal aroundthe dosage form. Although the elastomeric collets can be formed in avariety of shapes and sizes, in a preferred embodiment the elastomericcollets are generally circular and have a corrugated inside surface asshown in FIG. 39A. The inside surface comprises very small vent holes224 for air to vent through when the lower retainer 210 is mated withthe center mold assembly 212 and flowable material is injected over thetop portion of the dosage form. The vent holes 224 are relatively smallso that the flowable material injected over the dosage form from thecenter mold assembly 212 will generally not flow through the vent holes224.

As shown in FIGS. 36–39A disposed about the elastomeric collet 220 areflexible fingers 223. The flexible fingers 223 are mounted within thelower retainer 210 by any suitable means and are attached to the supportstem 222 to move up and down with the movement of the support stem 222,as best understood by comparing FIGS. 36 and 37. The flexible fingerscan be coupled to the center support stem by any of a variety offastening techniques.

In the preferred embodiment shown, the flexible fingers 223 are metaland spring radially outward when pushed out as shown in FIGS. 37 and 38,so that a dosage form can be received by or released from an elastomericcollet 220. The flexible fingers 223 move radially inward when retractedby the center support stem 222 as shown in FIGS. 36 and 37 to hold thedosage form within the elastomeric collet 220 firmly. Since the fingersmove radially inward they also provide a centering function. Theflexible fingers 223 fit between the elastomeric collet 220 and theflanged outer sleeve 218 so that when the lower retainer 210 is matedwith the center mold assembly 212, the dosage form is tightly held inplace and a seal is created around the dosage form. When an uncoateddosage form is being transferred to the lower retainer 210 or apartially coated dosage form is being transferred from the lowerretainer 210 to the center mold assembly 212, the center support stem222 moves to an upward position as shown in FIG. 36 and the flexiblefingers 223 expand radially outward. Expansion of the flexible fingers223 allows the elastomeric collet 220 to expand as shown in FIG. 38.Radial expansion and contraction of the dosage form holder 217 can beaccomplished by alternative means. For example the flexible fingers 223can be replaced by rigid fingers that pivot on bearings and are actuatedby cam followers. Alternatively linear bearings and plungers arranged ina radial fashion can move or collapse in the radial direction.Mechanisms similar to the shutter of a camera or inflatable bladders inthe shape of an inner tube or torus can also provide similar actions andmovements.

An actuator assembly 225 that includes in a preferred embodiment aspring 228, a plate 227, a linear bearing 237 and a small cam follower229 as best shown in FIG. 31 can be used to accomplish the verticalmovement required to close or open the dosage form holder 217. The plate227 is mounted to the support stem 222 so that movement of the plate 227in the vertical direction moves the support stem 222. In a preferredembodiment, there is one plate 227 for every eight support stems 222, asshown in FIG. 31. The spring 228 biases the plate 227 and therefore thesupport stems 222 to an upward position as shown in FIG. 36 in which thedosage form is not sealed within the dosage form holder 217. Duringrotation of the rotor 202, the small cam follower 229 rides in small camtrack 215, which causes the plate 227 to move down to seal the dosageform in the dosage form holders 217 as shown in FIG. 37. After molding,the small cam follower 229 along with the spring 228 causes the plate227 to move upward and release the dosage forms.

Because the flowable material is injected from above the dosage form, asviewed in FIGS. 34 and 37, the edge 226 of the elastomeric collet stopsflow of the flowable material. Consequently, only the portion of thedosage form 12 shown in FIG. 36 that is above the elastomeric collet 220will be coated when the lower retainer 210 and center mold assembly 210are mated. This permits a first flowable material to be used to coat onepart of the dosage form, and a second flowable material to coat theremainder of the dosage form—that portion which is beneath theelastomeric collet. Although the elastomeric collet is shaped so thatabout half of the dosage form will be coated at one time, theelastomeric collet can be of any desired shape to achieve a coating ononly a certain portion of the dosage form.

When two halves of a dosage form are coated with different flowablematerials, the two flowable materials may be made to overlap, or ifdesired, not to overlap. With the present invention, very precisecontrol of the interface between the two flowable materials on thedosage form is possible. Accordingly, the two flowable materials may bemade flush with each other with substantially no overlap. Or the twoflowable materials may be made with a variety of edges, for example toallow the edges of the flowable materials to interlock.

Any suitable controls including without limitation mechanical,electronic, hydraulic or pneumatic can be used to move the lowerretainer. In a preferred embodiment the controls are mechanical andinclude a large cam follower 231, large cam track 211 and actuator arm235. The large cam follower 231 rides in large cam track 211 and movesup and down within the large cam track. The actuator arm connects thelarge cam follower to the lower retainer so that movement of the largecam follower up and down causes the lower retainer to move up and down.Thus, as rotor 202 rotates the lower retainer 210 rotates with the rotor202 and the large cam follower 231 moves along the large cam track 211,which is stationary. When at a position to receive dosage forms, thelower retainer 210 is in a down position as shown in FIGS. 36 and 38.After dosage forms have been transferred to the lower retainer 210, thesupport stems 220 move down due to actuation of cam follower 229 andactuator assembly 225 to seal the dosage forms in the lower retainer 210as shown in FIGS. 37 and 39.

Following this, the large cam follower 231 causes the lower retainer 210to move up and mate with the center mold assembly as shown in FIG. 34.Once mated, the dosage form is partially coated in the center moldassembly 212. Continued rotation of the rotor 202 causes the large camfollower 231 to move down in the large cam track 211, which then causesthe lower retainer 210 to lower and separate from the center moldassembly 212 back to the position in FIGS. 31 and 35. In addition,rotation of the rotor 202 also causes the actuator 225 to move thesupport stems 222 as described above. The support stem 222 moves torelease the dosage forms just prior to or simultaneously with the lowerretainer moving downward to separate from the center mold assembly 212.Thus, the lower retainer functions to receive dosage forms, hold dosageforms while being partially coated in the center mold assembly 212, andtransfer dosage forms to the center mold assembly after they have beenpartially coated.

2. The Center Mold Assembly

The center mold assembly 212 is rotatably mounted to the rotor 202 on anaxis that is radial to the rotor. That is, the axis of rotation of thecenter mold assembly is perpendicular to the axis of rotation of therotor. The arrangement allows the center mold assembly to rotate 180degrees (end for end) at a prescribed time while the thermal cyclemolding module 200 is simultaneously revolving about its vertical axis.Preferably, the center mold assembly 212 is mounted so that it iscapable of rotating 180 degrees in either direction. Alternatively, thecenter mold assembly can be mounted so that it rotates 180 degrees in afirst direction and then rotates a further 180 degrees. FIG. 30 depictsseveral center mold assemblies 212 in a plan view. All of the centermold assemblies 212 are similarly mounted.

The center mold assembly comprises a series of back-to-back, identicalinsert assemblies 230. See FIGS. 32–35, 41 and 42. The center moldassembly 212 rotates partially coated dosage forms from their downwardlyoriented positions to upwardly oriented positions. The upwardly pointingportions of the dosage forms, which have been coated with flowablematerial, can now receive the remainder of their coatings once thecenter mold assembly 212 mates with the upper mold assembly 214. Also,the insert assemblies previously pointing upward now point downward.Thus they are now in a position to mate with the lower retainer 210 toreceive uncoated dosage forms.

Rotation of the center mold assembly may be accomplished, for example,using the system shown in FIG. 40. Depicted in FIG. 40 are cam followercarriage 215, cam track ring 285 comprising an upper groove 283 andlower groove 281, linkage 279, shaft 213, and rotor 202. As shown, thelinkage 279 is geared and shaft 213 has a geared portion, such that theshaft 213 will rotate as the linkage 279 moves up and down. The uppergroove 283 and lower groove 281 of the cam track ring 285 are connectedto each other by an “X” or crisscross pattern as shown in FIG. 40. This“X” pattern occurs at one location on the cam track ring. This allowsthe cam follower carriage 215 to follow the lower groove 281 during afirst revolution (360 degrees) of the thermal cycle molding module 200.On a second revolution, the cam follower carriage 215 follows the uppergroove 283. After 720 degrees of rotation the cam follower carriage 215switches back to the lower groove 281 and the cycle repeats.

The groove pattern shown moves the linkage 279 up and down duringrotation of the rotor to control the rotation of the shaft 213 andtherefore the center mold assembly 212. Thus, as the cam followercarriage 215 moves down, the linkage 279 moves down and the shaft 213and center mold assembly 212 rotate counter clockwise as shown in FIG.40. Similarly, when the cam follower carriage 215 moves up, the linkage279 moves up and drives the shaft 213 and center mold assembly 212 torotate clockwise. Each center mold assembly 212 is similarly mounted toa cam follower carriage 215, so that each center mold 212 will similarlyrotate first 180 degrees clockwise at the point where the upper andlower grooves cross, and then upon another revolution of the rotor 202the center molds rotate 180 degrees counterclockwise.

The cam follower carriage 215 has a pivot point 215D upon which it ismounted to the linkage 279. Attached to the cam follower carriage 215are three cam followers 215A, 215B, 215C which ride in the groove of thecam track ring 285. The use of three cam followers (215A, 215B, 215C,)assures that the cam follower carriage 215 follows the correct pathacross the “X” crossing point of the cam track ring 285, because the gapat the crossing point is shorter than the distance between any two camfollowers. Upon crossing of the gap two of the three cam followersremain engaged in the cam track, while the third follower crosses theunsupported region at the crossing point. The path takes the form of aflattened or folded figure eight. The lower groove 281 is the bottomloop of the figure eight and the upper groove 283 forms the top loop.

Flowable material is preferably heated and cooled in the center moldassembly as follows. Each center mold assembly 212 further includes avalve actuator assembly 232, a dosage form transfer actuator assembly241, and a plurality of manifold plates 234, 236. See FIGS. 43–47. Firstmanifold plates 234 and second manifold plates 236 house insert assembly230, as shown in FIGS. 43 and 46.

Defined within the first manifold plate 234 is a continuous channel 238that defines a coolant/heating flow path, as shown in FIGS. 43 and 44.Channel 238 traverses around the insert assembly 230. In a preferredembodiment the coolant/heating fluid is water but any suitable heattransfer fluid may be employed. First manifold plate 234 may also haveinlet and outlet ports 242 through which the coolant can flow through tothe channels 238. Ports 242 couple the coolant channels 238 to the heattransfer system described below. The first manifold plate 234 may bemounted by any suitable means in the center mold assembly 212, one ofwhich is by mechanical fasteners.

Preferably, hot fluid flows through the channels 238 to heat the centermold assemblies 212 just prior to and during the injection of theflowable material. Heating can begin prior to or after enclosing thedosage forms within the mold assemblies. Then, simultaneously with orafter injection of the flowable material into the mold assemblies, theheat transfer fluid is preferably switched from hot to cold to solidifythe flowable material.

The second manifold plate 236 comprises a plurality of holes 248 thatare aligned with holes 240 in the respective first manifold plate 234,so that an insert assembly 230 can be fixed within the holes 240, 242.The second manifold plate 236 also comprises channels 250 as shown inFIG. 47. The flowable material flows through the channels 250 to theinsert assembly 230, which directs the flowable material to the dosageforms. Flowable material connector ports 252 may also be included withinthe second manifold plate 236 that allow connection of tubing 208 tochannels 250. Thus, flowable material can be injected from the reservoir206 through the tubing 208, ports 252, channels 250 and to the insertassembly 230.

As shown in FIGS. 46 and 47, the second manifold plate 236 mayoptionally comprise a heating flow path 236B to warm the insert assembly230 and maintain the flowable material temperature above its meltingpoint. Depending on the type of flowable material used, this heating mayor may not be needed. For example, some flowable materials need to berelatively warm to exhibit good flow properties. Heating flow path 236Bcirculates through the second manifold plate 236 and connects to ports236A. From the ports, tubing (not shown) can be used to connect theheating flow path 236B to a heat exchanger that maintains the heatingfluid warm. Preferably, the heating fluid is water.

Each insert assembly 230 preferably comprises a stationary part, whichincludes a center insert 254, and a moveable part, which is in essence anozzle and comprises a valve body 260, a valve stem 280 and valve bodytip 282, as shown best in FIGS. 41 and 48–50. Although FIGS. 48–50illustrate one nozzle or valve assembly, in a preferred embodiment thereare preferably sixteen such nozzles or valve assemblies per center moldassembly 212, eight facing the upper mold assembly and eight facing thelower retainer. FIG. 49 depicts the insert assembly 230 in its closedposition. FIG. 48 shows the insert assembly 230 positioned for injectionof flowable material. FIG. 50 illustrates the insert assembly 230 in thedosage form transfer position.

The center insert 254 may be mounted to the first manifold plate 234 byany suitable means, and is preferably sealed with o-rings 262 andgrooves 264 to prevent leakage of flowable material, as shown in FIG.48. The coolant channels 238 are defined between the first manifoldplate 234 and the center insert 254. The center insert 254 isconstructed from a material that has a relatively high thermalconductivity, such as stainless steel, aluminum, berylium-copper,copper, brass, or gold. This ensures that heat can be transferred fromthe heat transfer fluid through the center insert to the flowablematerial. Heating ensures that the flowable material will flow into thecenter mold insert upon injection, and cooling at least partiallyhardens the flowable material. Depending on the type of flowablematerial used, however, heating may not be needed.

Each center insert 254 comprises a center cavity 266 within it, thesurface of which defines the final shape of the dosage form. In apreferred embodiment, center cavity 266 covers about half of a dosageform and is designed such that when mated with the lower retainer 210 orupper mold assembly 214 the dosage form will be covered and sealed.Center cavities 266 can be appropriately shaped and sized based on theparameters of the dosage form. Moreover, the surface of the centercavities may be designed to form coatings having a variety of features,i.e., dimple patterns (similar to a golf ball), holes, symbols includingletters and numbers, or other shapes and figures. Use of the centercavities described herein also permits precise control over thethickness of the molded coating. In particular, with the present thermalcycle molding module 200 coatings having thicknesses of about 0.003 toabout 0.030 inches may be consistently obtained.

In a preferred embodiment, an air passage 239 is also disposed throughthe first manifold plate 234. See FIG. 45. Compressed air is fed throughthe air passage 239 and used to assist in ejection of the coated dosageform from the center mold assembly 212 to the upper mold assembly 214.Although air is preferred for this purpose, the invention is not limitedthereto. An alternative ejector means, such as an ejector pin, may beused. The air can be pressurized to a relatively small pressure and canbe provided from air banks or the like that lead to a connection port inthe first manifold plate 234.

The movable portion of the insert assembly 230 includes the valve body260, the valve stem 280, and the valve body tip 282. See FIG. 48. Thevalve stem 280 is independently moveable. The valve stem 280 and valvebody 260 are slidably mounted within the insert assembly 230. In thepreferred embodiment shown, a plurality of o-rings 284 and grooves 286seal the moveable portions of the insert assembly to the stationaryportion of the insert assembly. Disposed around the valve stem 280 andthe valve body tip 282 is a flowable material path through whichflowable material traveling through the second manifold plate 236 flowswhen the insert assembly is in the open position (FIG. 48).

Although the center mold assembly 212 is constructed with identicalinsert assemblies 230 on both sides of its rotary axis, each insertassembly 230 performs a different function depending on whether it isoriented in the up or in the down position. When facing down, the insertassemblies 230 are actuated to inject flowable material to coat a firstportion of a dosage form. The insert assemblies 230 that are facing upare presenting partially coated dosage forms to the upper mold assembly214. During this time, the upward facing insert assemblies are in aneutral position. Prior to the molds opening however, the upward facinginsert assemblies are actuated to allow compressed air to enter thecenter cavity 266. This ejects the now completely coated dosage formsfrom the upward facing insert assemblies. Thus the completed dosageforms remain seated or held in the upper mold assembly 230.

Advantageously, the center mold assembly is designed to be actuated withjust one valve actuator assembly 232 and just one air actuator assembly241 (FIGS. 41 and 42). The valve actuator assembly 232 only actuates theinsert assemblies 230 that are facing down, while the air actuatorassembly 241 actuates only those insert assemblies 230 facing up.

Downward facing valve stem 280 is spring loaded to the closed positionof FIG. 49 by spring 290. Downward facing valve stem 280 is moveablebetween the closed position of FIG. 49 and the open position of FIG. 48by valve actuator assembly 232 shown in FIG. 41. In the preferredembodiment shown, the valve actuator assembly 232 comprises an actuatorplate 292 and cam follower 294 mounted thereto. Spring 290 is mountedwithin the valve stem 280 to spring load the valve stem 280 to theclosed position. An end of the valve stem 280 is mounted within theactuator plate 292 as shown in FIG. 41, so that the valve stem will movewith the actuator plate 292. Actuator plate 292 is mounted to move upand down as viewed in FIG. 41. Cam follower 294 is shown in FIGS. 31 and41. It rides in the cam track 274 disposed around the rotor 202. Camfollower 294 moves up and down according to the profile of cam track 274to move the actuator plate 292 and thereby control movement of thedownward facing valve stem 280.

Actuator plate 292 moves upward and opens the downward facing insertassemblies as viewed in FIG. 48 by moving and pulling the downwardfacing valve stems 280 against the bias of spring 290 from the positionof FIG. 49 to the position of FIG. 48. Opening of the downward facingvalve stems ports flowable material to dosage forms disposed between thecenter mold assembly 212 and the lower retainer 210. Following this, camfollower 294 and actuator plate 292 move down to release the downwardfacing valve stems 280. Due to the bias of spring 290, the downwardfacing valve stems 280 move to the closed position of FIG. 49 to stopthe flow of flowable material.

When actuator plate 292 moves up as viewed in FIG. 48, the upward facinginsert assemblies 230 remain stationary and closed. The upward facingvalve stems 280 are compressed against spring 290 and do not open. Noflowable material is provided to the upward facing insert assemblies230. Dosage forms in the upward facing insert assemblies are coated bythe upper mold assembly 214, described below. Similarly, no air isprovided to the downward facing insert assemblies because dosage formsare only released from the upward facing insert assemblies.

After the flowable material has been ported and the downward facinginsert assemblies 230 return to the position of FIG. 49, cam followers246A and 246B and air actuator plate 277 (FIG. 42) initiate movement ofthe valve body tip 282 and valve stem 280 of the upward facing insertassemblies 230. This provides a path for air through the center moldinsert. In particular, the upward facing valve body tip 282 and valvestem 280 move from the position of FIG. 49 to the position of FIG. 50due to movement of cam followers 246A and 246B downward as viewed inFIG. 42. After the application of air, cam followers 246A and 246B movedownward with the air actuator plate 277, permitting the upward facinginsert assemblies 230 to return to the position of FIG. 49, ready foranother cycle. Air actuator plate 277 does not move the downward facinginsert assemblies 230 during this cycle. They do not receive air.

Air actuator plate 277 shown in FIG. 42 controls movement of the upwardfacing valve body tip 282, valve body 260 and valve stem 280 as follows.As shown in FIGS. 42, pins 282A extend inward with respect to the centermold assembly 212 and springs 282B are mounted around the pins 282A. Thesprings 282B press against the upward facing valve bodies 260 and arecompressed so that the upward facing valve body tip 282 and valve body260 are normally in the closed position (FIG. 49). Cam 246A and airactuator plate 277 move downward to compress the springs 282A and pushthe upward facing valve body 260 and valve body tip 282 against the biasof the springs 282B to the opened position (FIG. 50).

FIG. 50 depicts an upward facing insert assembly 230 in the transferposition. In this position, the upward facing valve stem 280 and valvebody tip 282 are withdrawn. The upward facing valve stem 280 restsagainst the upward facing valve body tip 282 to stop the flow offlowable material. With the valve body tip 282 withdrawn, however, airfrom can flow to the mold.

After the dosage forms have been transferred from the center moldassembly, the air actuator plate 277 returns up to release the upwardfacing valve body 260, valve body tip 282 and valve stem 280 to theclosed position of FIG. 49.

3. The Upper Mold Assembly

The upper mold assembly 214, which is shown in FIGS. 51–54, is similarin construction to half of the center mold assembly 212. Like the centermold assembly 212, the upper mold assembly 214 directs flowable materialto at least partially coat a dosage form. In particular, the upper moldassembly 214 has a plurality of upper insert assemblies 296 (eight inthe preferred embodiment) that mate with corresponding insert assemblies230.

Although the upper mold assembly is similar to the center mold assembly,the upper mold assembly does not rotate. Rather, the upper mold assembly214 moves vertically up and down to mate with the center mold assemblyvia suitable controls as best understood by comparing FIGS. 32–35.Preferably, cam follower 299, cam track 298, and connector arm 293 (FIG.51) are used to control the movement of the upper mold assembly 214.Small cam follower 289 and small cam track 288 control upper actuatorplate 291. Cam follower 299, cam track 298, small cam follower 289, andsmall cam track 288 are similar in construction to the correspondingelements of the lower retainer 210.

The upper mold assembly 214 moves during rotation of the rotor 202 viacam follower 299 to mate with the center mold assembly 212 as shown inFIGS. 32–35 and at least partially coat a dosage form. After this, thecam follower 299 separates the upper mold assembly 214 from the centermold assembly 212 so that the finished, fully coated dosage form can beejected and transferred from the thermal cycle molding module as shownin FIG. 35.

The upper mold assembly 214 comprises an upper second manifold plate 251that ports flowable material to upper insert assemblies 296 and issimilar in construction to the second manifold plate 236 of the centermold assembly 212. An upper first manifold plate 253 providescooling/heating to the upper insert assemblies 296 and is similar inconstruction to the first manifold plate 234 of the center mold assembly212.

A seal around each dosage form is preferably created by contact betweenthe upward facing insert assembly 230 of the center mold assembly 212and the upper insert assembly 296 of the upper mold assembly 214, asbest understood with reference to FIGS. 48–50. An upper insert assembly296 is depicted in FIGS. 52–54 in the closed, open and eject positions,respectively. Similar to the insert assemblies 230, each upper insertassembly 296 includes a stationary portion that includes an upper insert265 and a upper flanged insert 258 and a moveable portion that isbasically a nozzle. The latter comprises an upper valve body 273, uppervalve stem 297 and upper valve body tip 295. The upper valve stem 297 ismoveable between open and closed positions to control flow of theflowable material to the dosage form. The upper valve body, upper valvestem and upper valve body tip define the flow path for the flowablematerial.

Each upper cavity 272 is appropriately sized so that the flowablematerial can flow over the dosage form and provide a coating of thedesired thickness. Similar to the center cavity 266 of the center insert254, the upper cavity 272 of the upper insert 265 can be of any desiredshape and size or be provided with a surface pattern (such as dimples,letters, numbers, etc.).

One difference between the upper insert assembly 296 and the insertassembly 230 is that the upper valve body tip 295 forms part of the sealaround the dosage form as shown in FIGS. 52–54 and moves outward ratherthan inward to eject a dosage form after it has been fully coated. FIG.54 depicts the upper valve body tip 295 positioned to eject a dosageform. FIG. 52 depicts the upper valve body tip 295 positioned to receivea dosage form.

An upper valve actuator 275 that includes an upper actuator plate 291,linkage 291B and cam follower 289 as shown in FIG. 51 actuate the upperinsert assembly 296. In other embodiments, electronic or othermechanical controls can be used. The linkage 291B couples cam follower289 to the upper actuator plate 291. The upper actuator plate 291 has aportion 291D that extends beneath a plunger so that when the upperactuator plate 291 moves up (FIG. 53) it pulls on valve stem 297. Upperactuator plate 291 also rests on top of upper valve stem 297 so thatwhen the upper actuator plate 291 moves down, the plunger and the uppervalve stem 297 are pushed down (FIG. 54).

As the rotor 202 rotates, cam follower 289, riding in cam track 298,moves up, causing the upper actuator plate 291 to rise and pull uppervalve stem 297 against the bias of spring 269 and hence move it from theclosed position of FIG. 52 to the open position of FIG. 53. After this,cam follower 289 moves down and causes upper actuator plate 291 to moveupper valve stem 297 to the closed position of FIG. 52.

Next, cam follower 289 moves down and causes upper actuator plate 291 tomove further down. When upper actuator plate 291 moves down, itdepresses upper valve stem 297, which pushes upper valve body 273 andupper valve body tip 295 against the bias of spring 271. Upper valvebody tip 295 thus assumes the position of FIG. 54 to eject a dosageform. In addition, as upper valve body tip 295 moves down air is portedaround it from the compressed air path 267. As with the center moldassembly, compressed air in the upper mold assembly ensures that thecoated dosage form does not stick to the upper insert 265 when it isejected.

After the coated dosage form is ejected, it may be sent to a transferdevice, dryer, or other mechanism. Following this, cam follower 289 andupper actuator plate 291 move back up. This in turn moves upper valvestem 297 and upper valve body tip 295 back to the position of FIG. 52due to the bias of spring 271.

Similar to the center mold assembly, heated heat transfer fluid isdirected through the upper first manifold plate 253 and upper insertassembly 296 to heat them during injection of the flowable material.Chilled heat transfer fluid is directed through the upper first manifoldplate 253 and upper insert assembly 296 after the flowable material hasbeen injected to harden it. In addition, warm heat transfer fluid can besent through the upper second manifold plate 251 constantly to heat theflowable material above its melting point.

4. Temperature Control and Energy Recovery System

Preferably, the center and upper mold assemblies 212, 214 of the thermalcycle molding module are hot, i.e., above the melting point of theflowable material, when the flowable material is injected into them.This assists the flowable material in flowing. The mold assemblies arethen preferably cooled, i.e., to below the melting or settingtemperature of the flowable material, rather quickly to harden theflowable material.

In light of this cycle, a heat sink, a heat source and a temperaturecontrol system are preferably provided to change the temperature of themolds. Examples of heat sinks include but are not limited to chilledair, Ranque Effect cooling, and Peltier effect devices. Examples of heatsources include electric heaters, steam, forced hot air, Joule Thomsoneffect, ranque effect, ultrasonic, and microwave heating. In a preferredembodiment, a heat transfer fluid such as water or oil is used totransfer heat, while electric immersion heaters provide the heat sourcefor the heat transfer fluid. Preferably, electrically powered freonchillers provide the heat sink for the heat transfer fluid.

FIGS. 55 and 56 depict the preferred temperature control system 600 forthe center mold assemblies and upper mold assemblies. Although only onemold assembly 214/212 is depicted, all mold assemblies are connected tothe temperature control system in a similar fashion. Preferably, thetemperature control system 600 includes a tubing system 606 and valves620 to 623. Tubing system 606 includes a cold loop 608 for cooling moldassembly 214/212, and a hot loop 609 for heating them. Both loops sharea common flow passageway between “T” fitting 603 and “T” fitting 605.Defined within the common flow passageway between “T” fitting 603 and“T” fitting 605 is a flow path in the mold assembly 214/212. Valves 620to 623, which may be solenoid or mechanically operated, control the flowof cool or heated heat transfer fluid through the mold assembly 214/212.The system may also include a heater 610, which heats the hot loop, anda chiller 612, which provides a chilled fluid source for the cold loop.Outlet ports 612A and inlet ports 612B of the chiller and outlet ports610A and inlet ports 610B of the heater can be connected to multiplemolds, so that a single chiller and a single heater can support all ofthe upper molds 214 and center molds 212.

Valves 620 to 623 are initially in the position of FIG. 55. Valves 621and 623 of the hot loop 609 are open so that hot heat transfer fluid canflow and circulate through the mold assembly 214/212. In contrast, thevalves of the cold loop 620 and 622 are closed so that coolant cannotflow through that loop. After flowable material has been injected intothe hot mold assembly 214/212, the cycle is switched to the cooling modeby closing solenoid valves 620 and 622 of the hot loop and openingvalves 603 and 605 of the cold loop 608 (see FIG. 56). This blocks theflow of hot heat transfer fluid to the molds assembly 214/212, andstarts the flow of chilled heat transfer fluid therethrough. Preferably,the center mold assembly 212 and the upper mold assembly 214 are capableof cycling in the temperature range of about 0 to about 100° C. in about1 seconds to 30 seconds. In the preferred embodiment using gelatin at60% moisture content, the center and upper mold assemblies 212, 214cycle between about 35° C. and 20° C. in about 2 seconds.

The cold and hot heat transfer fluid thus flows in the common flowpassageway between “T” fittings 603 and 605. When the valves switch fromthe heating mode to the cooling mode, the volume of hot heat transferfluid enclosed within the common flow passageway is transferred to thecold side of the system. Conversely, hot heat transfer fluid trapped inthe common flow passageway is transferred into the cold loop when thevalves switch to the heating mode.

Although the volume of fluid in the common flow passageway is relativelysmall, and the cost of energy to heat and chill this volume of fluid isnot unreasonable for a commercial process, a more preferred, energyefficient, and cost effective temperature control system is depicted inFIGS. 57–59. This preferred temperature control system 600 includes thefollowing components additional to those described above: a fluidreservoir 630, a moveable piston 604 bisecting the fluid reservoir, andvalves 626 and 627. The fluid reservoir can be replaced with twocollapsible bladders (hot and cold), thus eliminating the need for thepiston 604. For ease of description, however, the reservoir and pistonembodiment is described herein. Valves 620, 621,622,623,626 and 627,which may be solenoid or mechanically operated, control the flow of coolor hot heat transfer fluid through the system. Each mold assembly214/212 has its own fluid reservoir 630, piston 604, and valves 620,621,622,623,626 and 627. Initially, the valves are in the position ofFIG. 57. Valves 620, 622, and 626 of the cold loop are open so that coolheat transfer fluid can flow to the mold assembly 214/212. In contrast,the valves of the hot loop 621, 623,627 are closed so that hot heattransfer fluid cannot flow through that loop. The piston 604 is forcedto the cold loop side by the position of the valves 626,622,623, and627.

When the system switches to heating mode the solenoid valves, which arecontrolled by an electronic signal or by mechanical (cam) actuation,close or open as shown in FIG. 58. Valves 620, 626, and 623 close andvalves 621, 622, and 627 open. This blocks the flow of cool heattransfer fluid from the cold loop to the mold assembly 214/212 andstarts the flow of hot heat transfer fluid through the mold assembly214/212. This permits the hot heat transfer fluid to shift piston 604 tothe position shown in FIG. 58. When piston 604 is in the far rightposition it is generally configured to contain a volume of liquid equalto fluid enclosed within the passageway between “T” fittings 603 and605. This volume is tunable by adjusting when the valves open and close,or by adjusting the volume of the fluid reservoir 630. When piston 604reaches its preselected rightmost position (FIG. 59) valves 622, 626,and 620 close and valves 621, 623, and 627 open. The fluid contained inthe fluid reservoir to the left of piston 604 is cold. Fluid to theright of piston 604 is hot and most of this hot fluid has been evacuatedfrom the cylinder. The heating mode of the system is now in progress inFIG. 59. When the system switches to cooling mode, piston 604 moves inthe opposite direction (to the left) and fills with hot fluid thusreversing the process just described. By preventing or minimizing hotheat transfer fluid from entering the chilled side and by preventingcold heat transfer fluid from entering the hot side, energy losses areminimized and the system is maximally efficient.

FIGS. 60A–64 depict a particularly preferred embodiment of thetemperature control system incorporating an automatic valve system 650.The automatic valve system 650 directs heat transfer fluid to energyrecovery bladders 651 and 652. The automatic valve system 650 replacesvalves 622 and 623 of the system described in FIGS. 57–59. Connectingenergy recovery bladders together is connection rod 653. Slidablymounted to the connection rod 653 is valve slide 654.

Operation of the automatic valve system 650 is best understood bycomparing FIGS. 60A through 64. In FIGS. 60A and 60B cold heat transferfluid is circulating and hot heat transfer fluid is not. The energyrecovery bladders are shifted to the right most position with hot heattransfer fluid filling bladder 652. Valve slide 654 is seated in itsright most position by a flanged portion 653A of connection rod 653allowing fluid to pass to the left.

In FIGS. 61 and 62, the temperature control system has just switchedfrom cooling mode to heating mode by switching valves 620 and 626 fromtheir open to closed positions. Valves 621 and 627 have switched fromclosed to open positions, allowing hot heat transfer fluid to beginflowing around loop 609. The pressure from the fluid in loop 609 forcesenergy recovery bladder 651 to fill and move to the left as shown inFIGS. 61 and 62. Simultaneously, energy recovery bladder 652 empties andmoves to left due to the linking of the bladders by connection rod 653.The valve slide 654 functions as a check valve and remains seated to theright due to pressure against its left face. As bladders 651 and 652continue to move to the left, flanged portion 653B of connection rod 653makes contact with the right face of valve slide 654, unseating it andshifting it to the left most position shown in FIGS. 63 and 64. Thetemperature control system is now in the heating mode. When thetemperature control system switches back from heating to cooling modethe cycle repeats and the bladders 651 and 652 move to the right.

As described above, valves 620 through 623 of the temperature controlsystem can be of various designs known in art, such as spool, plug,ball, or pinch valves. These valves can be actuated by suitable meanssuch as air, electrical solenoids, or by mechanical means such as camtracks and cam followers. In a preferred embodiment, the valves arepinch valves and are actuated by mechanical cam tracks and cam followersas the thermal cycle molding module rotates. Known pinch valves arerelatively simple devices comprising a flexible section of tubing and amechanism that produces a pinching or squeezing action on the tubing.This tubing is compressed or “pinched” to block fluid flow therethrough.Release of the tubing allows fluid to flow. Accordingly, the pinch valvefunctions as a two-way valve.

The pinch valves of the present temperature control system utilize arotary design to “pinch” and “unpinch” flexible tubing. As describedabove, the center mold assembly rotates clockwise and thencounterclockwise over an arc of 180 degrees. Feeding the center moldassembly are eight tubes 606 that supply heat transfer fluid (two supplyand two return lines for each mold assembly). FIGS. 65–67 depict arotary pinch valve assembly 660 of the invention. The rotary pinch valveassembly 660 comprises a valve anvil 661 fixed to shaft 662. Shaft 662is attached to center mold assembly 212 (not shown) so that it canrotate about the same axis. Rotatably mounted to shaft 662 is valvepinch arm 663A. A similar valve pinch arm 663B is also rotatably mountedto shaft 662 and is free to move independently of valve pinch arm 663A.Actuating the valve pinch arms are valve actuators 665A and 665B, whichmove cam follows 666A and 666B in the vertical direction. The verticalrise and fall of actuators 665A and 665B causes corresponding movementsof cam followers 666A and 666B, which imparts a rotational movement tovalve pinch arms 663A and 663B via gears 667A and 667B, which arerotatably mounted to valve anvil 661. Gears 667A and 667B reduce oramplify the rotational movement of the valve pinch arms 663A and 663B byan amount proportional to the gear ratio. Although gears 667A and 667Bare used in the preferred embodiment described here, in otherembodiments they can be dispensed with. Rotational movement of the valvepinch arms can be imparted directly by cam followers and actuators.

The counter clockwise rotation of valve pinch arms 663A and 663B aboutshaft 661 causes tubes 606B to be squeezed closed and tubes 606A toremain open. Conversely, clockwise rotation of valve pinch arms 663A and663B about shaft 661 causes tubes 606A to be squeezed closed and tubes606B to remain open. The position of the valves (open or closed) dependson whether the orientation of center mold assembly 212 is up or down. Itis also a requirement that the position of the valves remain unchanged(or controlled) as the center mold assembly makes its 180 degreerotation. As shown in FIG. 66, the circular cam track 669 allows camfollowers 666A and 666B to remain in their fully actuated positionswhile the rotary pinch valve assembly 660 rotates clockwise and counterclockwise 180 degrees. Cam followers 666A and 666B can transit eitherthe inner surface or outer surface of the circular cam track 669 asshown in FIG. 66.

Transfer Device

1. Structure of the Transfer Device

Known tablet presses use a simple stationary “take-off” bar to removeand eject tablets from the machine. Since the turrets of these machinesrotate at fairly high speeds (up to 120 rpm), the impact forces on thetablets as they hit the stationary take-off bar are very significant.Dosage forms produced on these machines must therefore be formulated toposses very high mechanical strength and have very low friability justto survive the manufacturing process.

In contrast with prior art devices, the present transfer device iscapable of handling dosage forms having a higher degree of friability,preferably containing little or no conventional binders. Thus, apreferred formulation for use with present invention comprises one ormore medicants, disintegrants, and fillers, but is substantially free ofbinders. Dosage forms having a very high degree of softness andfragility may be transferred from any one of the operating modules ofthe invention as a finished product using the transfer device, ortransferred from one operating module to another for further processing.

The present transfer device is a rotating device, as shown in FIGS. 3and 68. It comprises a plurality of transfer units 304. It is preferablyused for transferring dosage forms or inserts within a continuousprocess of the invention comprising one or more operating modules, i.e.,from one operating module to another. For example, dosage forms may betransferred from a compression module 100 to a thermal cycle moldingmodule 200, or from a thermal setting molding module 400 to acompression module 100. Alternatively, the transfer device can be usedto transfer dosage forms or other medicinal or non-medicinal productsbetween the devices used to make such products, or to discharge fragileproducts from such machines.

Transfer devices 300 and 700 are substantially identical inconstruction. For convenience, transfer device 300 will be described indetail below. Each of the transfer units 304 are coupled to a flexibleconveying means, shown here as a belt 312 (FIGS. 68 and 69), which maybe made of any suitable material, one example of which is a compositeconsisting of a polyurethane toothed belt with reinforcing cords ofpolyester or poly-paraphenylene terephthalamide (Kevlar®, E.I. dupont deNemours and Company, Wilmington, Del.). The belt runs around the innerperiphery of the device 300. The transfer units 304 are attached to thebelt 312 as described below.

The transfer device can take any of a variety of suitable shapes.However, when used to transfer dosage forms or inserts between operatingmodules of the present invention, transfer device is preferablygenerally dog bone shaped so that it can accurately conform to the pitchradii of two circular modules, enabling a precision transfer.

The transfer device can be driven to rotate by any suitable power sourcesuch as an electric motor. In a preferred embodiment, the transferdevice is linked to operating modules of the invention and is driven bymechanical means through a gearbox which is connected to the main drivemotor 50. In this configuration the velocity and positions of theindividual transfer units of the transfer device can be synchronizedwith the operating modules. In a preferred embodiment the drive trainincludes a drive pulley 309 and an idler pulley 311 which are in thepreferred embodiment disposed inside of the transfer device 300. Thedrive shaft 307 connects the main drive train of the overall linkedsystem to the drive pulley 309 of the transfer device. The drive shaft307 drives the drive pulley 309 to rotate as shown in FIG. 3 and 68. Thedrive pulley 309 has teeth 309A that engage teeth 308 disposed on theinterior of belt 312, which in turn rotates the transfer device. Theidler pulley 311 has teeth 311A that engage belt 312, which causes theidler to rotate with the belt 312. Other flexible drive systems, such aschains, linked belts, metal belts, and the like can be used to conveythe transfer units 304 of the transfer device 300.

As shown in FIGS. 68 and 69, attached to the outer periphery of thetransfer device 300 is a dog bone shaped cam track 310 which preciselydetermines the path for the belt and the transfer units. The radii ofthe cam track 310, the pitch distance between the transfer units 304,the pitch of the toothed belt 312, and the gear ratio between the drivepulley 309 and the main drive of the linked system are all selected suchthat the transfer device is precisely aligned with the operating moduleslinked to it. As each operating module rotates, the transfer deviceremains synchronized and phased with each, such that a precise andcontrolled transfer from one operating module to another is achieved.The velocity and position of the transfer unit 304 is matched to thevelocity and position of the operating module along the concave portionsof the cam track. Transfers are accomplished along this arc length. Thelonger the length of the arc, the greater the time available to completea transfer. Riding in cam track 310 are cam followers 305 suitablymounted to the transfer units (FIG. 70).

In a preferred embodiment of this invention, both the drive pulley 309and the idler pulley 311 are driven. FIGS. 68 and 69 depict a toothedpulley 350, a second toothed pulley 351 and a toothed belt 352. Pulleys350, 351 and belt 352 connect the rotation of the drive pulley 309 withthe rotation of the idler pulley 311. This advantageously eliminates anyslack side condition in the belt. Linking of pulleys 309 and 311 couldalso be accomplished using gears, gear boxes, line shafts, chains andsprockets or by synchronized electric motors.

A preferred transfer unit 304 is depicted in FIGS. 70–75, and generallyincludes a pair of plunger shafts 320, one or preferably more than onecam follower 322, a plurality of bearings 324 to retain the plungershafts 320, a spring 326, a plate 328 that secures the plunger shafts320 to cam follower 322 thereby controlling their movement, and aretainer 330. Preferably, each transfer unit 304 is attached to flexibleconveying means 312 in a cantilever configuration so that retainers 330are cantilevered over the path of the dosage forms. This allows formultiple rows of retainers in the transfer unit and keeps contaminationby dirty mechanical parts away from the dosage form and its subcomponents. Moreover, it allows the flexible conveying means to contactclosely the operating modules to which it is connected, thereby allowingfor a smooth transfer pathway.

Retainers 330 are preferably flexible and constructed from anelastomeric material so that when no dosage form is inserted into theretainer 330, the retainer 330 generally points radially inward as shownin FIG. 71. When a dosage form is pushed into the retainer 330, theretainer 330 flexes upward as shown in FIG. 72. The dosage form passesthe retainer 330 and releases it so that the retainer supports thedosage form in the transfer unit from below. A dosage form is ejectedfrom a transfer unit by pushing down on the dosage form, thereby flexingthe retainer and permitting the dosage form to be pushed out. Oncereleased, the retainer 330 flexes back to its radially inward positionso that it can receive another dosage form. In a preferred embodiment,the retainer 330 is circular and includes segmented fingers ofelastomeric material as shown in FIG. 71, but it need not be soconstructed. It need only be flexible enough to flex, hold the dosageform, and release the dosage form. Retainer 330 extends radially inwarda distance such that when the dosage form is pushed past it, it holdsthe dosage form in place until it is ejected by the plunger shafts 320,as described below.

Cam follower 322 is disposed towards the top of the transfer unit 304.It is mounted so that it can move up and down as shown in FIGS. 70–74.Plate 328 is coupled to cam follower 322. Spring 326 is connected totransfer unit 304 and biases the plate 328 and cam follower 322 to anupper position. Plate 328 is also coupled to each plunger shaft 320, sothat movement of the plate 328 will cause movement of the plunger shafts320.

Each plunger shaft 320 is mounted within the transfer unit 304 by aplurality of bearings 324 that permit vertical movement of the plungershafts 320. The plunger shafts 320 are mounted so that one end of eachplunger shaft 320 can move into the respective space in which a dosageform is retained to eject it from the retainer 330, as shown in FIG. 74.As described below, the plunger shafts 320 move in response to movementof the plate 328 and the roller bearing 322 to eject dosage forms fromthe transfer unit 304. The plunger shafts 320 and bearings 324 may bemade of any suitable material.

2. Operation of the Transfer Device

Operation of the transfer device is best understood with reference toFIGS. 3 and 70–75. A description of the operation of one transfer unit304 is provided, but it will be understood that the other transfer units304 operate in a similar fashion. Moreover, operation is described withrespect to transfer of a dosage form from a compression module to athermal cycle molding module, however, as stated above, transfer may beaccomplished between any two operating modules or other devices. Forexample, FIG. 76 depicts a transfer device 700 transferring an insertfrom a thermal setting mold module to a compression module. The soledifferences between transfer devices 300 and 700 are the geometry of thetransferred object and the geometry of the transfer unit holders.

The transfer device operates as follows. The transfer unit 304 passes bythe die table 114 of the compression module 100 and the two retainers330 of the transfer unit 304 become aligned with die cavities 132 thatare on a radial line, as shown on the left of FIG. 75. At the point ofalignment, lower punch 120 moves upward in unison with plunger shafts320 due to the cam tracks as described above. A dosage form 12 isejected into the retainers 330 of the transfer unit 304 as shown inFIGS. 72, 73 and 75. The dosage form flexes the retainer 330 until itmoves past the retainer 330 and is held in the transfer unit 304 by theretainer 330. Since the plunger shafts and lower punches capture thedosage form in a confined space with minimal clearance, the dosage formcan not rotate or move randomly, which could jam this or subsequentapparatus. The dosage form is therefore fully controlled before, during,and after transfer. Rotation of the transfer device 300 and die table114 of the compression module 100 are synchronized so that transferunits 304 will continually pass above the die cavities 132 and dosageforms will be continuously transferred to the transfer units 304.

Further rotation of the transfer device 300 by the drive pulley causesthe belt 312 and its attached transfer units 304 to rotate. Eventually,the transfer units 304 containing the dosage forms reach the lowerretainer 210 of the thermal cycle molding module 200, as shown in FIGS.3 and 75. Cam 310 is disposed between the center mold assembly 212 andthe lower retainer 210. The lower retainer 210 passes just beneath thetransfer units 304. Thus, the transfer units 304 become aligned with twoof the elastomeric collets 220 in the lower retainer. As the transferunit 304 moves along cam track 310, cam track 310 pushes on the camfollower 322, which pushes on plate 328. Plate 328 moves the plungershafts 320, which in turn move down and contact the dosage forms. Thiscontact pushes the dosage forms past the elastomeric collets, and thedosage forms move out and into the elastomeric collets 220. Lowerretainer 210 and the transfer device 300 are rotating at speeds thatpermit the dosage forms to be continuously transferred from the transferunits 304 to the lower retainers 210. As the retainers 330 move past thethermal cycle molding module, plunger shafts 320 return to theiroriginal upward position.

3. Rotational Transfer Device

In a preferred alternate embodiment of this invention, a rotationaltransfer device is employed. Such a device is useful for handling dosageforms that must be both transferred from one piece of equipment andreoriented, for instance from a horizontal position to a verticalposition, or vice versa. For example, two color gelcaps, elongateddosage forms in which the boundary between colors lies along the shortaxis of the dosage form (see FIG. 81), must be compressed horizontallyalong their long axis, but coated in a vertical position. Accordingly,gelcaps compressed in the present compression module 100 and coated thethermal molding module 200 must be both transferred from the compressionmodule and reoriented into a vertical position.

FIGS. 77–81 depict a preferred rotational transfer device 600, which issimilar in construction to the transfer devices 300 and 700. Liketransfer devices 300 and 700 the rotational transfer device 600 is arotating device as shown in FIGS. 77 and 79. It comprises a plurality ofrotatable transfer units 602 coupled to a toothed belt 604. Riding inthe shaped cam track 606 are cam followers 607 suitably mounted to thetransfer units 602.

Each transfer unit 602 consists of a dosage form holder 608 rotatablymounted in a housing. Connected to the housing is a shaft 616 (FIG. 80).Ejector pin assembly 612 slides on bearings 614 along shaft 616 and itsvertical movement is controlled by cam follower 618 and cam track 620.Within the housing is gear 622, which is attached to the shaft of thedosage form holder 608 and gear 623 which is attached to the shaft ofthe actuator arm 624. Attached to actuator arm 624 is cam follower 626which rides in cam track 628. The vertical rise and fall of cam track628 causes a corresponding movement of cam follower 626 which imparts arotational movement to actuator arm 624. As the actuator arm rotates,gears 622 and 623 amplify this rotation causing dosage form holder 608to rotate by an amount proportional to the gear ratio. The geararrangement and offset design of the actuator arm keep the transferunits symmetrical about the vertical axis between cam followers 607.This symmetry of construction is required to assure proper tracking ofcam followers 618 and 626 and dosage form holder 608 as they transitthrough the various concave and convex radii of the rotational transferdevice 600.

One sequence of operations of the rotational transfer device 600 isdepicted in FIGS. 79–81. Elongated dosage forms (caplet 690) arecompressed horizontally in the compression module 100 and aretransferred through flexible retainers 630 into the dosage form holder608, which is also in a horizontal orientation (FIG. 80, FIGS. 81A, 81B,and 81E). Upon further transit through shaped cam track 606 the dosageform holder 608 rotates 90 degrees to a vertical orientation due tomotion of cam follower 626 within cam track 628 (FIGS. 81C and 81F).Upon reaching lower retainer 210 of thermal cycle molding module 200,caplet 690 is transferred through a second flexible retainer 630B viathe vertical movement of ejector pin assembly 612. Ejector pin assembly612 enters through holes 608A in dosage form holder 608 to evacuate thechamber 680 that holds caplet 690 (FIGS. 81C and F and FIGS. 81D and G).Caplet 690 is now transferred to the lower retainer 210 and upon furthertransit through the shaped cam track 606, the dosage form holder 608rotates 90 degrees, returning to its horizontal position to begin thecycle over again (FIG. 79).

Hardening Apparatus

Dosage forms that have been coated with flowable material in the thermalcycle molding module are relatively hard compared with dosage forms thathave coated using conventional dipping processes. Thus, the amount ofdrying needed after molding a coating onto a dosage form using thethermal cycle molding module is substantially less than that requiredwith known dipping processes. Nevertheless, they may still requirehardening, depending upon the nature of the flowable material.

Preferably, dosage forms coated in the thermal cycle molding module arerelatively hard so that they can be tumble hardened relatively quickly.Alternatively, an air dryer may be used. Any suitable dryers may beused. A variety are generally understood in the art.

Thermal Setting Molding Module

The thermal setting molding module may be used to make dosage forms perse, coatings, inserts for dosage forms, and the like from a startingmaterial in flowable form. The thermal setting molding module may beused as part of the overall system 20 of the invention (i.e., linked toother modules) or as a stand alone unit.

The thermal setting molding module 400 is a rotary apparatus comprisingmultiple hot injection nozzles and cold molding chambers. Each moldingchamber has its own nozzle. Advantageously, the volume of the moldingchambers is adjustable.

In a preferred embodiment of the invention, the thermal setting moldingmodule is used to make inserts for dosage forms. The inserts can be madein any shape or size. For instance, irregularly shaped inserts (ordosage forms per se) can be made, that is shapes having no more than oneaxis of symmetry. Generally however, cylindrically shaped inserts aredesired.

The inserts are formed by injecting a starting material in flowable forminto the molding chamber. The starting material preferably comprises anmedicant and a thermal setting material at a temperature above themelting point of the thermal setting material but below thedecomposition temperature of the medicant. The starting material iscooled and solidifies in the molding chamber into a shaped pellet (i.e.,having the shape of the mold). Injection and molding of the insertspreferably occurs as the thermal setting molding module 400 rotates. Ina particularly preferred embodiment of the invention, a transfer device700 (as described above) transfers shaped pellets from the thermalsetting molding module to a compression module 100 (also describedabove) as generally shown in FIG. 2, to embed the shaped pellets into avolume of powder before such powder is compressed into a dosage form inthe compression module.

The starting material must be in flowable form. For example, it maycomprise solid particles suspended in a molten matrix, for example apolymer matrix. The starting material may be completely molten or in theform of a paste. The starting material may comprise a medicant dissolvedin a molten material. Alternatively, the starting material may be madeby dissolving a solid in a solvent, which solvent is then evaporatedfrom the starting material after it has been molded.

The starting material may comprise any edible material which isdesirable to incorporate into a shaped form, including medicants,nutritionals, vitamins, minerals, flavors, sweeteners, and the like.Preferably, the starting material comprises a medicant and a thermalsetting material. The thermal setting material may be any ediblematerial that is flowable at a temperature between about 37 and about120° C., and that is a solid at a temperature between about 0 and about35° C. Preferred thermal setting materials include water-solublepolymers such as polyalkylene glycols, polyethylene oxides andderivatives, and sucrose esters; fats such as cocoa butter, hydrogenatedvegetable oil such as palm kernel oil, cottonseed oil, sunflower oil,and soybean oil; mono- di- and triglycerides, phospholipids, waxes suchas Carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax,microcrystalline wax, and paraffin wax; fat-containing mixtures such aschocolate; sugar in the form on an amorphous glass such as that used tomake hard candy forms, sugar in a supersaturated solution such as thatused to make fondant forms; low-moisture polymer solutions such asmixtures of gelatin and other hydrocolloids at water contents up toabout 30% such as those used to make “gummi” confection forms. In aparticularly preferred embodiment, the thermal setting material is awater-soluble polymer such as polyethylene glycol.

FIGS. 82–85 depict a preferred embodiment of the thermal setting moldingmodule 400. FIG. 82 is a side view, while FIGS. 83, 84 and 85A–D arefront views. The thermal setting molding module 400 generally includes amain rotor 402 as shown in FIGS. 3 and 82, on which are mounted aplurality of injection nozzle assemblies 404. Each injection nozzleassembly 404 includes a housing 406, which is shown in FIGS. 82–84,comprising a flow path 408 through which the starting material may flow.Mounted to each housing 406 are a plurality of nozzles 410. Although anynumber of nozzles may be employed in each injection nozzle assembly 404,preferably four are present. Mounted below each injection nozzleassembly 404 is a thermal mold assembly 420 comprising a plurality ofmolding chambers 422 that correspond to the nozzles 410 in eachinjection nozzle assembly 404.

A control valve 412, as shown in FIG. 83, is disposed within the housing406 for controlling the flow of starting material to each nozzle 410.Disposed above the valve 412 may be a valve seat 414 and a gasket 416for sealing the valve 412 when it is in the closed position. Each flowpath 408 is connected to a reservoir 418 of starting material.Preferably, reservoir 418 is pressurized and heated with a suitable typeof heater (such an electronic resistance or induction type heat) to atemperature whereby the starting material will flow. In a preferredembodiment where the starting material comprises a polymer such aspolyethylene glycol, the temperature of the starting material ismaintained between about 50 and 80° C. in the reservoir.

Mounted below the nozzles is a plate 428 as shown in FIGS. 82 and 85A–D.The plate 428 moves with nozzles 410 as shown in FIGS. 85A–D and asdescribed below. Disposed within the plate 428 are cooling channels 424for coolant fluid to flow around the plate 428. The nozzles arepreferably heated, for example by a heat transfer fluid deliveredthrough channels 430 in housing 406. Coolant is provided to the moldassembly 420 and the plates 428. As described below, coolant flowsthrough channels 424 in order to cool and thereby harden the injectedstarting material. Plates 428 are coupled to the housing 406 by anysuitable means and in the preferred embodiment mechanical fasteners canbe used.

As shown in FIG. 82, shafts 442 are preferably slidably mounted withinlinear bearings 440. Preferably two shafts are present. Disposed beneaththe housing 406 and around a portion of the shafts 442 that extend fromthe housing are springs 444. Shafts 442 extend beneath the springs 444as shown in FIGS. 85A–D into a block 446. As shown in FIGS. 82 and85A–D, and as described in more detail below, block 446 is moveable inresponse to a cam follower 448, thereby moving closer to housing 406 bycompressing springs 444.

As shown in FIGS. 85A–D, block 446 is mounted about two shafts 450 andmoves up and down with the shafts 450. Shafts 450, as is shown in FIGS.85A–D, are mounted within a bearing 452 that is coupled to cam follower448, which rides in a cam track of the type known in the art. As camfollower 448 travels around the thermal setting molding module 400 dueto rotation of the rotor 402, cam follower 448 rides up and down in thecam track. As cam follower 448 moves up and down, housing 406, plate 428and nozzles 410 also move. For instance, in FIG. 85A, cam follower 448is at a high point. As rotor 402 rotates, cam follower 448 rides down inthe cam track and moves the mechanically linked bearing 452 and block446 in the downward direction to the position shown in FIG. 85B. Housing406 and plate 428 also move. In this position, plate 428 is disposedproximate to molding chambers 422, but nozzles 410 are still disposedbelow the molding chambers 422.

Referring to FIG. 85C, continued rotation of rotor 402 moves camfollower 448 downward within the cam track. Plate 428, which is coupledto housing 406, cannot move downward because it is disposed against thethermal setting mold assembly 420. Consequently, block 446 exerts aforce on springs 444, compressing them. Block 446 pushes housing 406down into plate 428 and proximate the molding chambers 422. In thisposition, the starting material can be injected through the nozzles 410and into the molding chambers 422.

When housing 406 moves down as shown in FIG. 85C, control valve 412opens due to action of valve cam follower 417 in valve cam track 419.Starting material is ported through control valve 412 and nozzles 410 tofill mold chambers 422. Similarly, when cam follower 417 moves down fromthe position of FIG. 85C to the position of FIG. 85D, control valve 412closes to stop the flow of starting material. In a preferred embodimentof the invention, valve 412 is designed to provide a “suck back” actionupon closing. As shown in FIGS. 83 and 84, the valve seat 414 preferablyhas the geometry of a gradually tapering hole extending from edge 414Ato bottoming point 414B. As gasket 416, which is preferably made of anelastomeric material, moves to a closed position it enters the taperedvalve seat 414 and creates a seal against the wall of the valve seat414. As gasket 416 continues to move it acts like a piston forcing fluidin front of it and behind it to move upward as shown in FIG. 83. This inturn sucks back fluid from the tips of the nozzles 410, which assuresthat no starting material drools from or accumulates on the tips of thenozzles. The volume of starting material sucked back by movement ofgasket 416 can be controlled and adjusted by the depth to which thegasket penetrates into the valve seat.

As shown in FIG. 82, the thermal setting mold assemblies 420 are mountedto the rotor 402 by any suitable means. In a preferred embodiment,mechanical fasteners are used. When used in conjunction with otheroperating modules, rotor 402 may be attached to a common drive systemwith the other modules, so that they rotate in synchronicity, preferablyby driven motor 50 as shown in FIG. 3.

A preferred embodiment of a thermal setting mold assembly 420 is shownin FIG. 86, which is a cross-section. Although one thermal setting moldassembly 420 is depicted, each of the thermal setting mold assemblies420 are preferably the same.

Each thermal setting mold assembly 420 preferably comprises a pluralityof molding chambers 422, which are empty volumetric spaces within thethermal setting mold inserts 423. Preferably, one thermal setting moldinsert 423 corresponds with each nozzle 410. In a preferred embodiment,there are four thermal setting mold inserts 423 aligned with each offour nozzles 410, as best understood with reference to FIGS. 82 and 85.Although the molding chambers 422 may be any shape and size suitable formolding, they are preferably generally cylindrically shaped.

Disposed within each thermal setting mold insert 423 is a piston 434. Itwill be appreciated from FIG. 86 that placement of piston 434 within theeach thermal setting mold insert 423 defines the volume of the moldcavity 422. By specifically sizing each mold cavity 422 and adjustingthe position of piston 434, a desired volume and therefore proper dosageof the starting material is obtained.

Preferably, the pistons 434 are adjustably controlled by the position ofcam follower 470 and associated cam track 468. Pistons 434 are attachedto piston attachment block 436 by suitable mechanical means so thatpistons 434 move with piston attachment block 436. Piston attachmentblock 436 slides along the shafts 464 up and down. Preferably, there aretwo shafts 464 as shown in FIG. 86. Mounted to piston attachment block436 is cam follower 470. One or more springs 466 bias piston attachmentblock 436 and therefore pistons 434 into the inject position as viewedin FIG. 85C. As thermal setting mold assembly 420 travels with rotor402, cam follower 468 riding in its cam track actuates pistons 434 intothe eject position, which empties the molding chamber in preparation forthe next cycle (FIG. 85D).

Accordingly, during operation of the thermal setting molding module 400,nozzles 410 move up during rotation of the thermal setting moldingmodule 400 and inject a starting material into molding chambers 422.Next, starting material is hardened within the molding chambers 422 intoshaped pellets. Nozzles 410 are then retracted from the moldingchambers. All of this occurs as the molding chambers 422 and nozzles 410are rotating. After the starting material has hardened into shapedpellets, it is ejected from the molding chambers. See FIGS. 87 and 88.

When used with a transfer device 700 according to the invention, thetransfer device 700 rotates between the molding chambers 422 and plate428. The retainers 330 of the transfer device 700 receive the shapedpellets and transfers them to the another operating module, for examplea compression module 100. In the case of coupling a thermal settingmolding module 400 with a compression module 100 via a transfer device700, transfer device 700 inserts a shaped pellet into each die cavity132 after the fill zone 102 but before the compression zone 106 of thecompression module. It will be appreciated that a linked thermal settingmolding module 400, transfer device 700 and compression module 100 aresynchronized so that a shaped pellet is placed into each die cavity 132.The process is a continuous one of forming shaped pellets, transferringthe shaped pellets, and inserting the shaped pellets.

The thermal setting molding module has several unique features. One isthe ability to mass produce shaped pellets relatively rapidly, inparticular molded dosage forms comprising polymers that are typicallysolids or solid-like between about 0 and about 35° C. The thermalsetting molding module accomplishes this is by heating the startingmaterial prior to injecting it into the molding chambers and thencooling the starting material after injection.

Another unique feature of the thermal setting molding module is theadjustable volume of the molding chambers. Adjustability and tuning ofvolume and therefore weight is especially advantageous for theproduction of shaped pellets comprising high potency or highlyconcentrated drugs, which are dosed in small amounts. Another advantageof the thermal setting molding module is that it can employ liquids.Unlike a particulate solid, such as powders typically used to makedosage forms, the volume of a liquid is relatively invariable atconstant temperature. Density variations, which are troublesome inpowder compression, are therefore avoided with liquids. Very accurateweights, especially at very low weights (i.e. with starting materialscomprising high potency medicants) are achievable. Moreover, blenduniformity is also less assured with solid powders. Powder beds tend tosegregate based on differences in particle size, shape, and density.

Another advantage of the thermal setting molding module is that it moldsstarting material while continuously rotating. This permits itsintegration with other continuously operating rotary devices, resultingin a continuous process. Conventional molding operations are typicallystationary and have one nozzle feeding multiple mold cavities. Runnersare often formed using in conventional equipment. By providing a nozzlefor each molding chamber, runners are eliminated. Preferably, onecontrol valve controls multiple nozzles. This simplifies the design ofthe thermal setting molding module, reducing cost. The thermal settingmolding module may, of course be designed to operate without rotation ofthe rotor, for example on an indexing basis whereby a stationary groupof nozzles engages molding chambers on a indexing rotary turn table or alinear recalculating indexing belt or platen system. However, by using arotary system higher output rates can be achieved since products arecontinuously produced.

Specific embodiments of the present invention are illustrated by way ofthe following examples. This invention is not confined to the specificlimitations set forth in these examples, but rather to the scope of theappended claims. Unless otherwise stated, the percentages and ratiosgiven below are by weight.

In the examples, measurements were made as follows.

Coating thickness is measured using an environmental scanning electronmicroscope, model XL 30 ESEM LaB6, Philips Electronic InstrumentsCompany, Mahwah, Wis. Six tablets from each sample are measured at 6different locations on each tablet, as shown in FIG. 89.

Location 1: center of first major face, t_(c1)

Locations 2 and 3: edges (near punch land) of intersection between firstmajor face and side, t_(c2) and t_(c3)

Location 4: center of second major face, t_(c4)

Locations 5 and 6: edges (near punch land) of intersection betweensecond major face and side, t_(c5) and t_(c6)

Overall dosage form thickness and diameter are measured for 20 dosageforms using a calibrated electronic digital caliper. For thickness, thecaliper is positioned across t as shown in FIG. 89. For diameter, thecaliper is positioned at the midsections of the widest point of thedosage form sides shown in FIG. 89 as d.

EXAMPLE 1

A series of tablets having a molded gelatin coating thereon were madeaccording to the invention as follows.

Part A: Compressed Tablets

The following ingredients were mixed well in a plastic bag: 89.4 partsacetaminophen USP (590 mg/tablet) and 8.0 parts of synthetic wax X-2068T20 (53 mg/tablet). Next, 2.1 parts of sodium starch glycolate(EXPLOTAB) (13.9 mg/tablet) and 0.09 parts of silicon dioxide (0.6mg/tablet) were added to the bag, and mixed well. Then 0.36 parts ofmagnesium stearate NF (2.4 mg/tablet) were added to the bag, and theingredients were again mixed. The resulting dry blend was compressedinto tablets on a compression module according to the invention using7/16 inch extra deep concave tablet tooling.

The resulting tablets had an average weight of 660 mg, thickness of0.306 inches, and hardness of 3.2 kp.

The tablets from Part A were conveyed to a thermal cycle molding moduleaccording to the invention via a transfer device also according to thepresent invention. The tablets were coated with red gelatin on one halfthereof, and yellow gelatin on the other half thereof.

The red gelatin coating was made as follows. Purified water (450 g),Opatint Red DD-1761 (4.4 g), and Opatint Yellow DD-2125 (1.8 g) weremixed at room temperature till uniform. 275 Bloom Pork Skin Gelatin (150g) and 250 Bloom Bone Gelatin (150 g) were added together in a separatecontainer. The dry gelatin granules were manually stirred to mix. Thepurified water/Opatint solution was added to the gelatin granules, andmixed for about 1 minute to completely wet the gelatin granules. Thegelatin slurry was placed in a water bath and heated to 55 C to melt anddissolve the gelatin. The gelatin solution was held at 55 C forapproximately 3 hours (holding times at this temperature can generallyrange between about 2 and about 16 hours). The solution was then mixeduntil uniform (about 5 to 15 minutes), and transferred to a jacketedfeed tank equipped with a propeller-type electric mixer. The gelatinsolution was maintained at 55 C with continuous mixing during its use inthe thermal cycling molding module.

The yellow gelatin coating was made as follows. Purified water (450 g),and Opatint Yellow DD-2125 (6.2 g) were mixed at room temperature tilluniform. 275 Bloom Pork Skin Gelatin (150 g) and 250 Bloom Bone Gelatin(150 g) were added together in a separate container. The dry gelatingranules were stirred manually to mix. The purified water/Opatintsolution was added to the gelatin granules, and mixed for about 1 minuteto completely wet the gelatin granules. The gelatin slurry was placed ina water bath and heated to 55 C to melt and dissolve the gelatin. Thegelatin solution was held at 55 C for approximately 3 hours (holdingtimes at this temperature can generally range between about 2 and about16 hours). The solution was then mixed until uniform (about 5 to 15minutes), and transferred to a jacketed feed tank equipped with apropeller-type electric mixer. The gelatin solution was maintained at 55C with continuous mixing during its use in the thermal cycling moldingmodule.

EXAMPLE 2

Coating thickness was measured for samples of the following tablets:

A. Extra Strength Tylenol GelTabs

B. Excedrine Migrane Geltabs

C. Tablets of produced according to Example 1.

The results are shown in Table 1 below.

TABLE 1 A B C average coating thick- 145.17 microns 220.40 microns195.37 microns ness at major faces (locations 1, 4) for 6 tabletsvariability in coating  10.12%  5.01%  8.79% thickness at major faces(locations 1, 4) for 6 tablets average coating thick-    85 microns244.83 microns 209.62 microns ness (locations 1–6 for 6 tablets) coatingthickness var-  52.71%  12.64%  18.49% iability (rsd for loca- tions 1–6for 6 tablets) average coating thick-  54.92 microns 257.05 microns216.74 microns ness at edges coating thickness var-  19.80  11.88  20.56iability at edges (rsd for locations 2, 3, 5, 6 for 6 tablets) averagedifference in  63.25%  16.99%  15.93% coating thickness be- tween majorface and edge (location 1–loca- tion 2, location 4–loca- tion 5) maximumdifference    72%  33.4%  40.6% in coating thickness between major faceand edge (location 1– location 2, location 4– location 5) minimumdifference in    54%   7.1%   4.1% coating thickness be- tween majorface and edge (location 1–loca- location 2, location 4– location 5)Thicknesses and diameters of 20 coated tablets from each of the threesamples were also measured. The results are summarized in Table 2 below:

TABLE 2 A B C average coated tablet thickness at  7.67 mm  6.55 mm  7.99mm major faces (across locations 1, 4) for 20 tablets variability incoated tablet thickness 0.407% 1.44% 0.292% at major faces (locations 1,4) for 20 tablets average coated tablet diameter (across 11.46 mm 12.58mm 11.74 mm locations 7, 8 for 20 tablets) variability in coated tabletdiameter 0.183% 0.476% 0.275% (rsd across locations 7, 8 for 20 tablets)

EXAMPLE 3

Compressed tablets were prepared according the method described inExample 1. Press settings were held constant for a period of 7 hours, 47minutes. Tablets were sampled every 15 minutes. The resulting tabletshad the following properties:

Weight (mg) (average): 603.5 Weight (mg) (minimum): 582.2 Weight (mg)(maximum): 615.2 Weight (relative standard deviation (%)) 1.619Thickness (inches) (average): 0.293 Thickness (inches) (minimum): 0.29Thickness (inches) (maximum): 0.30 Thickness (relative standarddeviation (%)) 1.499 Hardness (kp) (average): 1.713 Hardness (kp)(minimum): 1.12 Hardness (kp) (maximum): 3.16 Hardness (relativestandard deviation (%)) 21.8

EXAMPLE 4

A flowable material suitable for coating a compressed dosage form wasmade as follows. The flowable material may be applied using a thermalcycle molding module according to the invention.

Material % w/w PEG 1450 (part 1) 30.0 PEG 1450 (part 2)   30–50%Polyethylene Oxide 300,000 15.0–25% Glycerin   0–10% Red color solution*(3% w/w)  5 *Red color solution Propylene Glycol (4.85) Red #40 dye(0.15)

Polyethylene glycol (PEG) 1450 (part 1) and polyethylene oxide (PEO)300,000 were shaken in a plastic bag until powders were mixed evenly.The (5 qt) bowl of a planetary mixer (Hobart Corp., Dayton, Ohio) washeated to 80 C by circulating hot water. PEG 1450 (part 2) was pouredinto the bowl and melted to form a liquid. The color solution, andoptionally, the glycerin were added while mixing at low speed. ThePEG/PEO powder mixture was added and the mixture mixed for 15 minutes.The resulting mixture was allowed to stand in the Hobart bowl for 2hours while maintaining the temperature at 80 C Cast films(approximately 0.8 mm thick) were prepared using a stainless steel mold(2″×5″×0.8 mm). The solution was transferred to a jacketed beaker (80 C)and de-aerated by vacuum for 6 hours. A second film was prepared usingthe same mold.

Increasing PEO from 15 to 25% (with corresponding decrease in PEG from85 to 75%) increased yield stress (maximum force per unit area which canbe applied before the film will deform permanently), and increasedstrain (% film elongation at break point).

Decreasing glycerin from 10% to 2% increased Tensile Strength (force perunit area required to break the film). Deaerating theglycerin-containing films prior to casting generally decreased tensilestrength.

EXAMPLE 5

Another flowable material suitable for coating a compressed dosage formwas made as follows. The flowable material may be applied using athermal cycle molding module according to the invention.

Material % w/w PEG 1450 granular 70–75% Polyethylene Oxide 600,000 15%White beeswax  5–10% Red color solution* (3% w/w) 5 *Red color solutionPropylene Glycol (4.85) Red #40 dye (0.15)

The (5 qt) bowl of a planetary mixer (Hobart Corp., Dayton, Ohio) washeated to 80 C by circulating hot water. PEG 3350 granular was pouredinto the bowl and melted to form a liquid. The white beeswax, colorsolution, and polyethylene oxide were added while mixing at low speed.The resulting mixture was mixed for a total of 12 minutes, then allowedto stand in the Hobart bowl for 2 hours while maintaining thetemperature at 80 C Cast films were prepared using a glass slide. Thesolution was transferred to a jacketed beaker (80 C) and de-aerated byvacuum for 6 hours. A second film was prepared using the same mold.

The white beeswax formula had increased tensile strength compared to theglycerin formulas.

Examples 4 and 5 illustrate suitable formulations for the flowablematerial. Advantageously, these formulations are solvent (includingwater) free. This eliminates the need to evaporate solvent from coatingsmade from such formulations, shortening and simplifying drying.Accordingly, in one embodiment of the invention, the flowable materialis substantially solvent-free, that is contains less than about 1 weightpercent, preferably no, solvent.

1. A method of making a dosage form containing a first medicant, whichcomprises a) injecting through a nozzle that moves for injection andthen retracts away from a mold cavity to close the mold cavity aflowable material containing said first medicant into said mold cavity,wherein the nozzle comprises valve body and tip, and after injection,the nozzle is retracted and the tip closes the mold cavity; and b)hardening by cooling within the mold cavity said flowable material intoa solid molded dosage form having a shape substantially the same as themold cavity, wherein substantially all of the flowable material injectedinto the mold cavity becomes part of the solid molded dosage form. 2.The method of claim 1, further comprising the step of heating saidflowable material prior to injecting said flowable material into saidmold cavity, and wherein said hardening step (b) comprises cooling saidflowable material.
 3. The method according to claim 2, wherein said moldcavity is heated prior to said injecting step (a) and cooled during saidhardening step (b).
 4. The method according to claim 3, wherein saidmold cavity is heated and cooled using heat transfer fluids thatcirculate proximal to said mold cavity.
 5. The method of claim 2,wherein said mold cavity is heated prior to said injection step (a) andcooled during said hardening step (b) using a single heat transfer fluidheated by a heat source and cooled by a heat sink.
 6. The methodaccording to claim 1, wherein said flowable material comprises apolymer.
 7. The method according to claim 1, wherein said flowablematerial comprises a carbohydrate.
 8. The method according to claim 1,wherein said flowable material comprises a fat.
 9. The method accordingto claim 1, wherein said flowable material comprises a wax.
 10. Themethod according to claim 1, wherein said flowable material comprisesgelatin.
 11. The method according to claim 10, further comprisingheating said gelatin to a temperature above its gel point prior to saidinjecting step (a), and wherein said hardening step (b) comprisescooling said gelatin to a temperature below its gel point.
 12. Themethod of claim 1, wherein said molded dosage form is substantially freeof visible defects.
 13. The method according to claim 1, furthercomprising the step of placing an insert in said mold cavity prior tosaid injecting step (a), such that said molded dosage form comprises aninsert embedded therein.
 14. The method according to claim 13, whereinsaid insert comprises a polymer.
 15. The method according to claim 13,wherein said insert comprises a carbohydrate.
 16. The method accordingto claim 13, wherein said insert comprises a fat.
 17. The methodaccording to claim 13, wherein said insert comprises a wax.
 18. Themethod according to claim 13, wherein said insert comprises a secondmedicant.
 19. The method according to claim 1 performed while said moldcavity is traveling along a circular path.
 20. A method of making amolded dosage form which comprises a) heating a flowable materialcontaining a pharmaceutical active ingredient; b) injecting saidflowable material through a nozzle that moves for injection and thenretracts away from a mold cavity to close the mold cavity wherein thenozzle comprises a valve body tip, and after injection, the nozzle isretracted and the tip closes the mold cavity having an orifice into saidmold cavity; and c) hardening said flowable material into a solid moldeddosage form having a shape substantially the same as the mold cavity;wherein said hardening step (c) comprises cooling said flowable materialand wherein said mold cavity is heated prior to said injecting step (b)and cooled during said hardening step (c), wherein substantially all ofthe flowable material injected into the mold cavity becomes part of thesolid molded dosage form.
 21. The method of claim 20, wherein a medicantis introduced into the mold cavity prior to said hardening step (c). 22.The method of claim 1 or 13, wherein the flowable material issubstantially solvent-free.